P38 map kinase inhibitors

Provided herein, inter alia, are p38 mitogen-activated protein kinase inhibitors and methods of treating cancer using p38 mitogen-activated protein kinase inhibitors.

The Sequence Listing written in file 048440-724001US_SL_ST25.txt, created Jun. 12, 2020, 15,833 bytes, machine format IBM-PC, MS Windows operating system, is hereby incorporated by reference.

BACKGROUND

Mitogen-activated protein kinases are involved in various cellular responses to extracellular signals. Members of this family are Ser/Thr kinases that activate their substrates by phosphorylation. Mitogen-activated protein kinases are activated by a variety of signals including growth factors, cytokines, UV radiation, and stress-inducing agents. One particularly interesting mitogen-activated protein kinases is p38. p38, also known as cytokine suppressive anti-inflammatory drug binding protein and RK, has been isolated from murine pre-B cells that were transfected with the lipopolysaccharide receptor, CD14, and induced with LPS. p38 has since been isolated and sequenced, as has the cDNA encoding it in humans and mouse. Activation of p38 has been observed in cells stimulated by stress, such as treatment of lipopolysaccharides, UV, anisomycin, or osmotic shock, and by cytokines, such as IL-1 and TNF.

Inhibition of p38 kinase leads to a blockade on the production of both IL-1 and TNF. IL-1 and TNF stimulate the production of other proinflammatory cytokines such as IL-6 and IL-8 and have been implicated in acute and chronic inflammatory diseases and in post-menopausal osteoporosis. Based upon this finding, it is believed that p38, along with other mitogen-activated protein kinases, have a role in mediating cellular response to inflammatory stimuli, such as leukocyte accumulation, macrophage/monocyte activation, tissue resorption, fever, acute phase responses and neutrophilia. In addition, mitogen-activated protein kinases, such as p38, have been implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and neurodegenerative disorders. Inhibitors of p38 have also been implicated in the area of pain management through inhibition of prostaglandin endoperoxide synthase-2 induction. Drugs that specifically inhibit p38 mitogen-activated protein kinases are being developed. However, the efficacy of these p38 MAP kinase inhibitors is still being investigated. Accordingly, there is a need in the art to develop potent inhibitors of p38 MAP kinase that are useful in treating various conditions associated with p38 activation. Described herein, inter alia, are solutions to these and other problems in the art.

BRIEF SUMMARY

The disclosure provides oligonucleotides of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, and homologs of each of the foregoing. In aspects, the oligonucleotides are ribonucleic acids. In aspects, the oligonucleotides are miRNA, mRNA, siRNA, or saRNA. In aspects, the oligonucleotides are aptamers that inhibit a p38γ mitogen-activated protein kinase. In aspects, the oligonucleotides are aptamers that inhibit phosphorylation of the p38γ mitogen-activated protein kinase.

The disclosure provides methods of inhibiting phosphorylation of p38γ mitogen-activated protein kinase by contacting p38γ mitogen-activated protein kinase with an effective amount of the oligonucleotide of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or a homolog of any one of the foregoing. In aspects, the oligonucleotides are ribonucleic acids. In aspects, the oligonucleotides are miRNA, mRNA, siRNA, or saRNA.

The disclosure provides method of treating cancer in a patient in need thereof by administering to the patient a effective amount the oligonucleotide of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or a homolog of any one of the foregoing. In aspects, the oligonucleotides are ribonucleic acids. In aspects, the oligonucleotides are miRNA, mRNA, siRNA, or saRNA. In aspects, the oligonucleotides are aptamers that inhibit a p38γ mitogen-activated protein kinase. In aspects, the oligonucleotides are aptamers that inhibit phosphorylation of the p38γ mitogen-activated protein kinase. In aspects, the cancer is breast cancer (e.g., triple negative breast cancer), prostate cancer, colon cancer, ovarian cancer, lymphoma (e.g., cutaneous T-cell lymphoma), bladder cancer, thyroid cancer, lung cancer, or head and neck squamous cell carcinoma.

The disclosure provides methods of suppressing proliferation of a cutaneous T-cell lymphoma cell by contacting the cutaneous T-cell lymphoma cell with an effective amount of the oligonucleotide of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or a homolog of any one of the foregoing. In aspects, the oligonucleotides are ribonucleic acids. In aspects, the oligonucleotides are miRNA, mRNA, siRNA, or saRNA.

The disclosure comprises complexes comprising: (i) a p38γ MAP kinase, and (ii) an oligonucleotide of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, or a homolog of any one of the foregoing. In aspects, the oligonucleotides are ribonucleic acids. In aspects, the oligonucleotides are miRNA, mRNA, siRNA, or saRNA.

These and other embodiments and aspects of the disclosure are described herein.

DETAILED DESCRIPTION

Definitions

The terms “p38 kinase,” “p38 mitogen-activated protein kinase,” “p38 MAP kinase,” and/or “p38” are here used interchangeably and according to their common, ordinary meaning and refer to proteins of the same or similar names and functional fragments and homologs thereof. The term includes recombinant or naturally occurring forms of, or variants thereof, that maintain p38 kinase activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to p38 kinase). The p38 kinases have four isoforms including p38α (MAPK14, SEQ ID NO:11), p38β (MAPK11, SEQ ID NO:12), p38γ (MAPK12, SEQ ID NO:13), and p38δ (MAPK13, SEQ ID NO:14). The role of p38 MAP kinases in cancer is described, for example, by Koul et al, Genes Cancer, 4(9-10):342-359 (2013).

The terms “p38alpha (p38α)” or “mitogen-activated protein kinase 14 (MAPK14)” (e.g. Protein Data Bank ID: 5ML5 or SMQV; SEQ ID NO:11) are here used interchangeably and according to their common, ordinary meaning and refer to proteins of the same or similar names and functional fragments and homologs thereof. The term includes any recombinant or naturally occurring form of, or variants thereof that maintain p38α activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to p38α).

The terms “p38beta (p38β)” or “mitogen-activated protein kinase 11 (MAPK11)” (e.g. Protein Data Bank ID: 3GC7, 3GC8 or 3GC9; SEQ ID NO:12) are here used interchangeably and according to their common, ordinary meaning and refer to proteins of the same or similar names and functional fragments and homologs thereof. The term includes any recombinant or naturally occurring form of, or variants thereof that maintain p38β activity (e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to p38β).

The terms “p38gamma (p38γ)” or “mitogen-activated protein kinase 12 (MAPK12)” (e.g., Protein Data Bank ID: 4QUM or 4QUN; SEQ ID NO:13) are here used interchangeably and according to their common, ordinary meaning and refer to proteins of the same or similar names and functional fragments and homologs thereof. The term includes any recombinant or naturally occurring form of, or variants thereof that maintain p38γ activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to p38γ).

The terms “p38delta (p38δ)” or “mitogen-activated protein kinase 13 (MAPK13)” (e.g. Protein Data Bank ID: 4MYG, 5EKN or 5EKO; SEQ ID NO:14) are here used interchangeably and according to their common, ordinary meaning and refer to proteins of the same or similar names and functional fragments and homologs thereof. The term includes any recombinant or naturally occurring form of, or variants thereof that maintain p38δ activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to p386).

The terms “p38 inhibitors” or “p38 kinase inhibitors” or “p38 MAP kinase inhibitors” are agents (e.g. compounds) that reduce the activity, levels and/or expression of p38 relative to the absence of the inhibitor. In aspects, these p38 kinase inhibitors can sufficiently inhibit the activities of one or more p38 related protein kinases or proteins in p38 related signal transduction cascades. In aspects, the p38 kinase inhibitors sufficiently suppress or downregulate the expression of p38 kinases, for example, by affecting or suppressing transcription level of mRNA of p38 kinase, protein expression level thereof or other indications for related genes thereof. Non-limiting examples of the p38 inhibitors include small molecules (e.g. synthetic small molecules or natural products and derivatives thereof), antibodies (e.g. monoclonal antibodies), nucleic acids (e.g. siRNA, microRNA and anti-microRNA), and peptides. In aspects, the p38 inhibitor comprises SEQ ID NO:1 or a homolog thereof. In aspects, the p38 inhibitor comprises SEQ ID NO:2 or a homolog thereof. In aspects, the p38 inhibitor comprises SEQ ID NO:3 or a homolog thereof. In aspects, the p38 inhibitor comprises SEQ ID NO:4 or a homolog thereof. In aspects, the p38 inhibitor comprises SEQ ID NO:5 or a homolog thereof. In aspects, the p38 inhibitor comprises SEQ ID NO:6 or a homolog thereof. In aspects, the p38 inhibitor comprises SEQ ID NO:7 or a homolog thereof. In aspects, the p38 inhibitor comprises SEQ ID NO:8 or a homolog thereof.

The term “aptamer” as provided herein refers to oligonucleotides (e.g., short oligonucleotides or deoxyribonucleotides), that bind (e.g. with high affinity and specificity) to proteins, peptides, and small molecules. In aspects, the aptamer is a ribonucleic acid that binds to a p38 MAP kinase. In aspects, the aptamer is a ribonucleic acid that binds to a p38γ MAP kinase. In aspects, the aptamer is a ribonucleic acid that selectively and with high affinity binds to a p38γ MAP kinase over other isoforms of p38 MAP kinase, such as p38α, p38β, and p38δ. Aptamers may have secondary or tertiary structure and, thus, may be able to fold into diverse and intricate molecular structures. Aptamers can be selected in vitro from very large libraries of randomized sequences by the process of systemic evolution of ligands by exponential enrichment (SELEX as described in Ellington A D, Szostak J W (1990)); in vitro selection of RNA molecules that bind specific ligands (Tuerk et al, Nature 346:818-822 (1990)); systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase (Science 249:505-510); or by developing SOMAmers (slow off-rate modified aptamers) (Gold (2010)). Aptamer-based multiplexed proteomic technology for biomarker discovery. (PLoS ONE 5(12):e15004). Applying the SELEX and the SOMAmer technology includes adding functional groups that mimic amino acid side chains to expand the aptamer's chemical diversity. As a result high affinity aptamers for almost any protein target are enriched and identified. Aptamers exhibit many desirable properties for targeted drug delivery, such as ease of selection and synthesis, high binding affinity and specificity, low immunogenicity, and versatile synthetic accessibility. To date, a variety of anti-cancer agents (e.g. chemotherapy drugs, toxins, and siRNAs) have been successfully delivered to cancer cells using apatmers.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In aspects, inhibition means negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In aspects, inhibition refers to reduction of a disease or symptoms of disease. In aspects, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In aspects, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In aspects, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).

In embodiments, the term “inhibition,” “inhibit,” “inhibiting” and the like means negatively affecting (e.g. decreasing or suppressing) the expression of the protein relative to the expression level of the protein in the absence of the inhibitor. In aspects, inhibition means negatively affecting (e.g. decreasing or suppressing) transcription or expression level of mRNA of the protein relative to the transcription or expression level of the mRNA of the protein in the absence of the inhibitor. In aspects, inhibition means negatively affecting (e.g. decreasing or suppressing) expression level of the protein relative to the expression level of the protein in the absence of the inhibitor by elevating or increasing a concentration of a biological molecule which negatively affecting (e.g. decreasing or suppressing) the expression level of the protein.

An amino acid residue in a protein “corresponds” to a given residue when it occupies the same essential structural position within the protein as the given residue.

The term “isolated”, when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

As may be used herein, the terms “nucleic acid,” “nucleic acid molecule,” “nucleic acid oligomer,” “oligonucleotide,” “nucleic acid sequence,” “nucleic acid fragment” and “polynucleotide” are used interchangeably and are intended to include, but are not limited to, a polymeric form of nucleotides covalently linked together that may have various lengths, either deoxyribonucleotides or ribonucleotides, or analogs, derivatives, or modifications thereof. Different polynucleotides may have different three-dimensional structures, and may perform various functions, known or unknown. Non-limiting examples of polynucleotides include a gene, a gene fragment, an exon, an intron, intergenic DNA (including, without limitation, heterochromatic DNA), messenger RNA (mRNA), transfer RNA, ribosomal RNA, a ribozyme, cDNA, a recombinant polynucleotide, a branched polynucleotide, a plasmid, a vector, isolated DNA of a sequence, isolated RNA of a sequence, a nucleic acid probe, and a primer. Polynucleotides useful in the methods of the disclosure may comprise natural nucleic acid sequences and variants thereof, artificial nucleic acid sequences, or a combination of such sequences.

A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T); (uracil (U) for thymine (T) when the polynucleotide is RNA). Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and/or modified nucleotides.

An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5′-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

The terms “numbered with reference to” or “corresponding to,” when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence.

The term “amino acid side chain” refers to the functional substituent contained on amino acids. For example, an amino acid side chain may be the side chain of a naturally occurring amino acid. Naturally occurring amino acids are those encoded by the genetic code (e.g., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine), as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. In aspects, the amino acid side chain may be a non-natural amino acid side chain. In aspects, the amino acid side chain is H,

“Nucleic acid” refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In aspects, “nucleic acid” does not include nucleosides. The terms “polynucleotide,” “oligonucleotide,” “oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term “nucleoside” refers, in the usual and customary sense, to a glycosylamine including a nucleobase and a five-carbon sugar (ribose or deoxyribose). Non limiting examples, of nucleosides include, cytidine, uridine, adenosine, guanosine, thymidine and inosine. The term “nucleotide” refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA. Examples of nucleic acid, e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA, and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and minicircle DNA, and any fragments thereof. The term “duplex” in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.

Nucleic acids, including e.g., nucleic acids with a phosphothioate backbone, can include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions. By way of example, the nucleic acid can include an amino acid reactive moiety that reacts with an amino acid on a protein or polypeptide through a covalent, non-covalent or other interaction.

The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, Oligonucleotides and Analogues: A Practical Approach, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine; and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Pat. Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, Carbohydrate Modifications in Antisense Research, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In aspects, the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

Nucleic acids can include nonspecific sequences. As used herein, the term “nonspecific sequence” refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence. By way of example, a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.

An “antisense nucleic acid” as referred to herein is a nucleic acid (e.g., DNA or RNA molecule) that is complementary to at least a portion of a specific target nucleic acid and is capable of reducing transcription of the target nucleic acid (e.g. mRNA from DNA), reducing the translation of the target nucleic acid (e.g. mRNA), altering transcript splicing (e.g. single stranded morpholino oligo), or interfering with the endogenous activity of the target nucleic acid. See, e.g., Weintraub, Scientific American, 262:40 (1990). Typically, synthetic antisense nucleic acids (e.g. oligonucleotides) are generally between 15 and 25 bases in length. Thus, antisense nucleic acids are capable of hybridizing to (e.g. selectively hybridizing to) a target nucleic acid. In aspects, the antisense nucleic acid hybridizes to the target nucleic acid in vitro. In aspects, the antisense nucleic acid hybridizes to the target nucleic acid in a cell. In aspects, the antisense nucleic acid hybridizes to the target nucleic acid in an organism. In aspects, the antisense nucleic acid hybridizes to the target nucleic acid under physiological conditions. Antisense nucleic acids may comprise naturally occurring nucleotides or modified nucleotides such as, e.g., phosphorothioate, methylphosphonate, and -anomeric sugar-phosphate, backbonemodified nucleotides.

In the cell, the antisense nucleic acids hybridize to the corresponding RNA forming a double-stranded molecule. The antisense nucleic acids interfere with the endogenous behavior of the RNA and inhibit its function relative to the absence of the antisense nucleic acid. Furthermore, the double-stranded molecule may be degraded via the RNAi pathway. The use of antisense methods to inhibit the in vitro translation of genes is well known in the art (Marcus-Sakura, Anal. Biochem., 172:289, (1988)). Further, antisense molecules which bind directly to the DNA may be used. Antisense nucleic acids may be single or double stranded nucleic acids. Non-limiting examples of antisense nucleic acids include siRNAs (including their derivatives or pre-cursors, such as nucleotide analogs), short hairpin RNAs (shRNA), micro RNAs (miRNA), saRNAs (small activating RNAs) and small nucleolar RNAs (snoRNA) or certain of their derivatives or pre-cursors.

A “siRNA,” “small interfering RNA,” “small RNA,” or “RNAi” as provided herein refers to a nucleic acid that forms a double stranded RNA, which double stranded RNA has the ability to reduce or inhibit expression of a gene or target gene when expressed in the same cell as the gene or target gene. The complementary portions of the nucleic acid that hybridize to form the double stranded molecule typically have substantial or complete identity. In aspects, a siRNA or RNAi is a nucleic acid that has substantial or complete identity to a target gene and forms a double stranded siRNA. In aspects, the siRNA inhibits gene expression by interacting with a complementary cellular mRNA thereby interfering with the expression of the complementary mRNA. Typically, the nucleic acid is at least about 20-100 nucleotides in length (e.g., each complementary sequence of the double stranded siRNA is 20-100 nucleotides in length, and the double stranded siRNA is about 20-100 base pairs in length). In aspects, the length is 25-90 base nucleotides, about 30-90 or about 40-80 nucleotides in length.

A “saRNA,” or “small activating RNA” as provided herein refers to a nucleic acid that forms a double stranded RNA, which double stranded RNA has the ability to increase or activate expression of a gene or target gene when expressed in the same cell as the gene or target gene. The complementary portions of the nucleic acid that hybridize to form the double stranded molecule typically have substantial or complete identity. In aspects, a saRNA is a nucleic acid that has substantial or complete identity to a target gene and forms a double stranded saRNA. Typically, the nucleic acid is at about 20-100 nucleotides in length (e.g., each complementary sequence of the double stranded saRNA is 20-100 nucleotides in length, and the double stranded saRNA is about 20-100 base pairs in length). In aspects, the length is 25-90 base nucleotides, about 30-90 or about 40-80 nucleotides in length.

The term “complement,” as used herein, refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanosine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence. The nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the coding sequence. A further example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.

As described herein the complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other, may have a specified percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region).

The phrase “specifically (or selectively) binds” to an antibody or “specifically (or selectively) immunoreactive with,” when referring to a protein or peptide, refers to a binding reaction that is determinative of the presence of the protein, often in a heterogeneous population of proteins and other biologics. Thus, under designated immunoassay conditions, the specified antibodies bind to a particular protein at least two times the background and more typically more than 10 to 100 times background. Specific binding to an antibody under such conditions requires an antibody that is selected for its specificity for a particular protein. For example, polyclonal antibodies can be selected to obtain only a subset of antibodies that are specifically immunoreactive with the selected antigen and not with other proteins. This selection may be achieved by subtracting out antibodies that cross-react with other molecules. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select antibodies specifically immunoreactive with a protein (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity).

The term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).

The word “expression” or “expressed” as used herein in reference to a gene means the transcriptional and/or translational product of that gene. The level of expression of a DNA molecule in a cell may be determined on the basis of either the amount of corresponding mRNA that is present within the cell or the amount of protein encoded by that DNA produced by the cell. The level of expression of non-coding nucleic acid molecules (e.g., siRNA) may be detected by standard PCR or Northern blot methods well known in the art. See, Sambrook et al., 1989 Molecular Cloning: A Laboratory Manual, 18.1-18.88.

The terms “Histone deacetylase (HDAC) inhibitors (HDACi or HDIs)” are used to indicate any molecules that sufficiently inhibit the activities (e.g. acetylation) of the histone deacetylases. In addition, these HDAC inhibitors inhibit activities (e.g. acetylation) of the proteins or enzymes included in nonhistone transcription factors and transcriptional co-regulators by increasing or repressing the transcription of genes such as ACTR, cMyb, E2F1, EKLF, FEN 1, GATA, HNF-4, HSP90, Ku70, NF-κB, PCNA, p53, RB, Runx, SF1 Sp3, STAT, TFIIE, TCF, YY1, and the like. Non-limiting examples of the HDAC inhibitors include HDAC5 inhibitor, HDAC6 inhibitor, HDAC10 inhibitor, and HDAC11 inhibitor. Non-limiting examples of the HDAC inhibitors include small molecules (e.g. synthetic small molecules or natural products and derivatives thereof), antibodies (e.g. monoclonal antibodies), nucleic acids (e.g. siRNA, microRNA and anti-microRNA), and peptides. Non-limiting examples of the small molecules as HDACi include HDAC inhibitors include vorinostat (SAHA), romidepsin, abexinostat, CI-994, belinostat, panobinostat, givinostat, entinostat, mocetinostat, trichostatin, SRT501, CUDC-101, JNJ-26481585, quisinostat, RGFP109 or PCI24781.

“Patient,” “subject,” “patient in need thereof,” and “subject in need thereof” are herein used interchangeably and refer to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In aspects, a patient is human.

Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.

“Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In aspects, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).

The term “contacting” may also include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a protein or enzyme. Contacting may include allowing a compound described herein to interact with a protein or enzyme that is involved in a signaling pathway.

As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein-activator interaction means positively affecting (e.g. increasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the activator. Activation may refer to reduction of a disease or symptoms of disease. Activation may refer to an increase in the activity of a particular protein or nucleic acid target. The protein may be cystic fibrosis transmembrane conductance regulator. Thus, activation includes, at least in part, partially or totally increasing stimulation, increasing, promoting, or expediting activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein.

The term “modulator” refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule.

The term “modulate” is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties. For example, a modulator of a target protein changes by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. A modulator of a disease decreases a symptom, cause, or characteristic of the targeted disease.

“Co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. The compounds can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g. to reduce metabolic degradation). The compositions can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Co-administration includes administering one active agent (e.g. a complex described herein) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent (e.g. anti-constipation or anti-dry eye agents). Also contemplated herein, are embodiments, where co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In aspects, the active agents can be formulated separately. The active and/or adjunctive agents may be linked or conjugated to one another. The compounds described herein may be combined with treatments for constipation and dry eye disorders.

The compositions disclosed herein can be delivered transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols. Oral preparations include tablets, pills, powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. The compositions n may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes. The compositions disclosed herein can also be delivered as microspheres for slow release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres, which slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or, as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). In aspects, the formulations of the compositions can be delivered by the use of liposomes which fuse with the cellular membrane or are endocytosed, i.e., by employing receptor ligands attached to the liposome, that bind to surface membrane protein receptors of the cell resulting in endocytosis. By using liposomes, particularly where the liposome surface carries receptor ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the compositions into the target cells in vivo. (See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). The compositions can also be delivered as nanoparticles.

Pharmaceutical compositions may include compositions wherein the active ingredient (e.g. compounds described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in methods to treat a disease, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule, and/or reducing, eliminating, or slowing the progression of disease symptoms.

The dosage and frequency (single or multiple doses) administered to a mammal can vary depending upon a variety of factors, for example, whether the mammal suffers from another disease, and its route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated, kind of concurrent treatment, complications from the disease being treated or other health-related problems. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds described herein. Adjustment and manipulation of established dosages (e.g., frequency and duration) are well within the ability of those skilled in the art.

The compounds described herein can be used in combination with one another, with other active drugs known to be useful in treating a disease (e.g. cancer or CTCL) or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent. Thus, the compounds described herein may be co-administered with one another or with other active drugs known to be useful in treating a disease.

The term “lymphoma” refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin's disease. Hodgkin's disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed-Sternberg malignant B lymphocytes. Non-Hodgkin's lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma. Exemplary T-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.

The term “cutaneous T-cell lymphoma” or “CTCL” refers to a typical T-cell lymphoma that involves skin, although CTCL also can involve the blood, the lymph nodes, and other internal organs. Non-limiting examples of CTCL include mycosis fungoides and Sézary syndrome. For instance, mycosis fungoides is the most common type of CTCL constituting half cases of all CTCLs, which may cause various skin symptoms such as patches, plaques, or tumors. Sézary syndrome is an advanced, variant form of mycosis fungoides, which can be characterized by the presence of lymphoma cells (e.g., B-cells or T-cells) in the blood.

Cancer model organism, as used herein, is an organism exhibiting a phenotype indicative of cancer, or the activity of cancer causing elements, within the organism. The term cancer is defined above. A wide variety of organisms may serve as cancer model organisms, and include for example, cancer cells and mammalian organisms such as rodents (e.g. mouse or rat) and primates (such as humans). Cancer cell lines are widely understood by those skilled in the art as cells exhibiting phenotypes or genotypes similar to in vivo cancers. Cancer cell lines as used herein includes cell lines from animals (e.g. mice) and from humans.

An “anticancer agent” as used herein refers to a molecule (e.g. compound, peptide, protein, nucleic acid, antibody) used to treat cancer through destruction or inhibition of cancer cells or tissues. Anticancer agents may be selective for certain cancers or certain tissues. In aspects, anticancer agents herein may include epigenetic inhibitors and multi- or specific kinase inhibitors.

An “epigenetic inhibitor” as used herein, refers to an inhibitor of an epigenetic process, such as DNA methylation (a DNA methylation Inhibitor) or modification of histones (a Histone Modification Inhibitor). An epigenetic inhibitor may be a histone-deacetylase (HDAC) inhibitor, a DNA methyltransferase (DNMT) inhibitor, a histone methyltransferase (HMT) inhibitor, a histone demethylase (HDM) inhibitor, or a histone acetyltransferase (HAT). Non-limiting examples of HDAC inhibitors include vorinostat (SAHA), romidepsin, abexinostat, CI-994, belinostat, panobinostat, givinostat, entinostat, mocetinostat, trichostatin, SRT501, CUDC-101, JNJ-26481585, quisinostat, RGFP109 or PCI24781. Examples of DNMT inhibitors include azacitidine and decitabine. Examples of HMT inhibitors include EPZ-5676. Examples of HDM inhibitors include pargyline and tranylcypromine. Examples of HAT inhibitors include CCT077791 and garcinol.

“Selective” or “selectivity” or the like of a compound refers to the compound's ability to discriminate between molecular targets (e.g. a compound having selectivity toward one or more of p38 kinases (p38α, p38β, p38γ and p38δ) or MAPK (e.g. MAPK 11, MAPK12, MAPK 13 and MAPK14)). In aspects, the ribonucleic acids described herein have selectivity for p38γ kinase over p38α, p38β, and p38δ kinases.

“Specific”, “specifically”, “specificity”, or the like of the ability of the ribonucleic acids described herein to cause a particular action, such as inhibition, to a particular molecular target with minimal or no action to other proteins in the cell (e.g., the ribonucleic acids described herein have specificity towards p38 gamma kinase (p38γ) or MAPK12 displays inhibition of the activity of those proteins including suppression of expression thereof as well as inhibition of enzyme properties). Meanwhile, the ribonucleic acids described herein display little-to-no inhibition of other p38 kinases such as p38α, p38β and p38δ or MAPK such as MAPK 11, MAPK 13 and MAPK14.

The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease means that the disease is caused by (in whole or in part), a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function, or a side-effect of the compound (e.g. toxicity) is caused by (in whole or in part) the substance or substance activity or function.

In embodiments, the disclosure provides a ribonucleic acid comprising the sequence: GGGAGACAAGAAUAAACGCUCAAGUGUUUUUGAAGCGUCAGCUAUAGUUGGUCUUC UUAGAGCUUCGACAGGAGGCUCACAACAGGC (SEQ ID NO:1). In SEQ ID NO:1, each U and each C is a 2F′-modified pyrimidine. In aspects, the disclosure provides a ribonucleic acid having at least 50% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 55% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 60% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 65% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 70% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 75% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 80% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 85% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 88% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 90% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 92% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 94% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 95% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 96% sequence identity to SEQ ID NO:1. In aspects, the ribonucleic acid has at least 98% sequence identity to SEQ ID NO:1. In aspects, the disclosure provides pharmaceutical compositions comprising any of the oligonucleotides described herein and a pharmaceutically acceptable excipient.

In aspects, the ribonucleic acid comprising SEQ ID NO:1 (and homologs thereof) is an miRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:1 (and homologs thereof) is an mRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:1 (and homologs thereof) is an siRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:1 (and homologs thereof) is an saRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:1 (and homologs thereof) is an aptamer. In aspects, the ribonucleic acid comprising SEQ ID NO:1 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:1 (and homologs thereof) is an aptamer that is capable of inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:1 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:1 (and homologs thereof) is an aptamer that is capable of inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:1 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:1 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the p38 mitogen-activated protein kinase is a p38γ mitogen-activated protein kinase. In aspects, the disclosure provides pharmaceutical compositions comprising any of the ribonucleic acids described herein and a pharmaceutically acceptable excipient.

In embodiments, the disclosure provides a ribonucleic acid comprising the sequence: GUGUUUUUGAAGCGUCAGCUAUAGUUGGUCUUCUUAGAGC (SEQ ID NO:2). In SEQ ID NO:2, each U and each C is a 2F′-modified pyrimidine. In aspects, the disclosure provides a ribonucleic acid having at least 50% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 55% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 60% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 65% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 70% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 75% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 80% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 85% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 90% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 92% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 94% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 95% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 96% sequence identity to SEQ ID NO:2. In aspects, the ribonucleic acid has at least 98% sequence identity to SEQ ID NO:2. In aspects, the disclosure provides pharmaceutical compositions comprising any of the oligonucleotides described herein and a pharmaceutically acceptable excipient. In aspects, the ribonucleic acid comprising SEQ ID NO:2 (and homologs thereof) is an miRNA, mRNA, siRNA, or saRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:2 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:2 (and homologs thereof) is an aptamer that is capable of inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:2 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:2 (and homologs thereof) is an aptamer that is capable of inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:2 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:2 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the p38 mitogen-activated protein kinase is a p38γ mitogen-activated protein kinase. In aspects, the disclosure provides pharmaceutical compositions comprising any of the ribonucleic acids described herein and a pharmaceutically acceptable excipient.

In embodiments, the disclosure provides a ribonucleic acid comprising the sequence: GGGAGACAAGAAUAAACGCUCAAAACAGCGUUUGCUAUAGUUGGUCUCUCCUAAUC AACGAGCUUCGACAGGAGGCUCACAACAGGC (SEQ ID NO:3). In SEQ ID NO:3, each U and each C is a 2F′-modified pyrimidine. In aspects, the disclosure provides a ribonucleic acid having at least 50% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 55% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 60% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 65% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 70% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 75% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 80% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 85% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 88% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 90% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 92% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 94% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 95% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 96% sequence identity to SEQ ID NO:3. In aspects, the ribonucleic acid has at least 98% sequence identity to SEQ ID NO:3. In aspects, the disclosure provides pharmaceutical compositions comprising any of the ribonucleic acids described herein and a pharmaceutically acceptable excipient.

In aspects, the ribonucleic acid comprising SEQ ID NO:3 (and homologs thereof) is an miRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:3 (and homologs thereof) is an mRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:3 (and homologs thereof) is an siRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:3 (and homologs thereof) is an saRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:3 (and homologs thereof) is an aptamer. In aspects, the ribonucleic acid comprising SEQ ID NO:3 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:3 (and homologs thereof) is an aptamer that is capable of inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:3 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:3 (and homologs thereof) is an aptamer that is capable of inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:3 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:3 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the p38 mitogen-activated protein kinase is a p38γ mitogen-activated protein kinase. In aspects, the disclosure provides pharmaceutical compositions comprising any of the ribonucleic acids described herein and a pharmaceutically acceptable excipient.

In embodiments, the disclosure provides a ribonucleic acid comprising the sequence: AACAGCGUUUGCUAUAGUUGGUCUCUCCUAAUCAACGAGC (SEQ ID NO:4). In SEQ ID NO:4, each U and each C is a 2F′-modified pyrimidine. In aspects, the disclosure provides a ribonucleic acid having at least 50% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 55% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 60% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 65% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 70% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 75% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 80% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 85% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 90% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 92% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 94% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 95% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 96% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 98% sequence identity to SEQ ID NO:4. In aspects, the disclosure provides pharmaceutical compositions comprising any of the oligonucleotides described herein and a pharmaceutically acceptable excipient. In aspects, the ribonucleic acid comprising SEQ ID NO:4 (and homologs thereof) is an miRNA, mRNA, siRNA, or saRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:4 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:4 (and homologs thereof) is an aptamer that is capable of inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:4 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:4 (and homologs thereof) is an aptamer that is capable of inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:4 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:4 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the p38 mitogen-activated protein kinase is a p38γ mitogen-activated protein kinase. In aspects, the disclosure provides pharmaceutical compositions comprising any of the ribonucleic acids described herein and a pharmaceutically acceptable excipient.

In embodiments, the disclosure provides a ribonucleic acid comprising the sequence: GGGAGACAAGAATAAACGCTCAACAATCAGCGCCATCGTTGGTTGGGGTGCTTGTTTC CTGCCTTCGACAGGAGGCTCACAACAGGC (SEQ ID NO:5). In SEQ ID NO:5, each U and each C is a 2F′-modified pyrimidine. In aspects, the disclosure provides a ribonucleic acid having at least 50% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 55% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 60% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 65% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 70% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 75% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 80% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 85% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 90% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 92% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 94% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 95% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 96% sequence identity to SEQ ID NO:5. In aspects, the ribonucleic acid has at least 98% sequence identity to SEQ ID NO:5. In aspects, the disclosure provides pharmaceutical compositions comprising any of the ribonucleic acids described herein and a pharmaceutically acceptable excipient.

In aspects, the ribonucleic acid comprising SEQ ID NO:5 (and homologs thereof) is an miRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:5 (and homologs thereof) is an mRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:5 (and homologs thereof) is an siRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:5 (and homologs thereof) is an saRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:5 (and homologs thereof) is an aptamer. In aspects, the ribonucleic acid comprising SEQ ID NO:5 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:5 (and homologs thereof) is an aptamer that is capable of inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:5 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:5 (and homologs thereof) is an aptamer that is capable of inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:5 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:5 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the p38 mitogen-activated protein kinase is a p38γ mitogen-activated protein kinase. In aspects, the disclosure provides pharmaceutical compositions comprising any of the ribonucleic acids described herein and a pharmaceutically acceptable excipient.

In embodiments, the disclosure provides a ribonucleic acid comprising the sequence: CAATCAGCGCCATCGTTGGTTGGGGTGCTTGTTTCCTGCC (SEQ ID NO:6). In SEQ ID NO:6, each U and each C is a 2F′-modified pyrimidine. In aspects, the disclosure provides a ribonucleic acid having at least 50% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 55% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 60% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 65% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 70% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 75% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 80% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 85% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 90% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 92% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 94% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 95% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 96% sequence identity to SEQ ID NO:6. In aspects, the ribonucleic acid has at least 98% sequence identity to SEQ ID NO:6. In aspects, the disclosure provides pharmaceutical compositions comprising any of the oligonucleotides described herein and a pharmaceutically acceptable excipient. In aspects, the ribonucleic acid comprising SEQ ID NO:6 (and homologs thereof) is an miRNA, mRNA, siRNA, or saRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:6 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:6 (and homologs thereof) is an aptamer that is capable of inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:6 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:6 (and homologs thereof) is an aptamer that is capable of inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:6 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:6 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the p38 mitogen-activated protein kinase is a p38γ mitogen-activated protein kinase. In aspects, the disclosure provides pharmaceutical compositions comprising any of the ribonucleic acids described herein and a pharmaceutically acceptable excipient.

In embodiments, the disclosure provides a ribonucleic acid comprising the sequence: GGGAGACAAGAATAAACGCTCAACGGGACAAAATCAGTGAGCGTTGTCACTTATTCGG TGGGCTTCGACAGGAGGCTCACAACAGGC (SEQ ID NO:7). In SEQ ID NO:7, each U and each C is a 2F′-modified pyrimidine. In aspects, the disclosure provides a ribonucleic acid having at least 50% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 55% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 60% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 65% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 70% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 75% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 80% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 85% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 90% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 92% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 94% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 95% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 96% sequence identity to SEQ ID NO:7. In aspects, the ribonucleic acid has at least 98% sequence identity to SEQ ID NO:7. In aspects, the disclosure provides pharmaceutical compositions comprising any of the ribonucleic acids described herein and a pharmaceutically acceptable excipient.

In aspects, the ribonucleic acid comprising SEQ ID NO:7 (and homologs thereof) is an miRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:7 (and homologs thereof) is an mRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:7 (and homologs thereof) is an siRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:7 (and homologs thereof) is an saRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:7 (and homologs thereof) is an aptamer. In aspects, the ribonucleic acid comprising SEQ ID NO:7 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:7 (and homologs thereof) is an aptamer that is capable of inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:7 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:7 (and homologs thereof) is an aptamer that is capable of inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:7 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:7 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the p38 mitogen-activated protein kinase is a p38γ mitogen-activated protein kinase. In aspects, the disclosure provides pharmaceutical compositions comprising any of the ribonucleic acids described herein and a pharmaceutically acceptable excipient.

In embodiments, the disclosure provides a ribonucleic acid comprising the sequence: CGGGACAAAATCAGTGAGCGTTGTCACTTATTCGGTGGGC (SEQ ID NO:8). In SEQ ID NO:8, each U and each C is a 2F′-modified pyrimidine. In aspects, the disclosure provides a ribonucleic acid having at least 50% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 55% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 60% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 65% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 70% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 75% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 80% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 85% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 90% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 92% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 94% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 95% sequence identity to SEQ ID NO:4. In aspects, the ribonucleic acid has at least 96% sequence identity to SEQ ID NO:8. In aspects, the ribonucleic acid has at least 98% sequence identity to SEQ ID NO:8. In aspects, the disclosure provides pharmaceutical compositions comprising any of the oligonucleotides described herein and a pharmaceutically acceptable excipient. In aspects, the ribonucleic acid comprising SEQ ID NO:8 (and homologs thereof) is an miRNA, mRNA, siRNA, or saRNA. In aspects, the ribonucleic acid comprising SEQ ID NO:8 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:8 (and homologs thereof) is an aptamer that is capable of inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:8 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting the activity of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:8 (and homologs thereof) is an aptamer that is capable of inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:8 (and homologs thereof) is an aptamer that is capable of binding to a p38 mitogen-activated protein kinase. In aspects, the ribonucleic acid comprising SEQ ID NO:8 (and homologs thereof) is an aptamer that is capable of binding to and inhibiting phosphorylation of a p38 mitogen-activated protein kinase. In aspects, the p38 mitogen-activated protein kinase is a p38γ mitogen-activated protein kinase. In aspects, the disclosure provides pharmaceutical compositions comprising any of the ribonucleic acids described herein and a pharmaceutically acceptable excipient.

The pharmaceutical compositions comprising the ribonucleic acids described herein may be prepared and administered in a wide variety of dosage formulations. Compounds described may be administered orally, rectally, or by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally).

For preparing pharmaceutical compositions from compounds described herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier may be a finely divided solid in a mixture with the finely divided active component. In tablets, the active component may be mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10,000 mg, or 0.1 mg to about 1,000 mg, or 0.1 mg to about 500 mg, according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.

Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01% and about 2% by weight. Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight.

The pharmaceutical compositions may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates.

The pharmaceutical composition may be intended for intravenous use. The pharmaceutically acceptable excipient can include buffers to adjust the pH to a desirable range for intravenous use. Many buffers including salts of inorganic acids such as phosphate, borate, and sulfate are known.

The pharmaceutical composition may include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated.

The dosage and frequency (single or multiple doses) of compounds administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated; presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds disclosed herein.

Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.

Dosage amounts and intervals can be adjusted individually to provide levels of the administered compounds effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.

Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.

Provided herein are methods of inhibiting phosphorylation of a p38γ mitogen-activated protein kinase by contacting the p38γ mitogen-activated protein kinase with a ribonucleic acid described herein (e.g., SEQ ID NO:1, SEQ ID NO:3, or a homolog thereof). In aspects, the p38γ mitogen-activated protein kinase is located within a cell. In aspects, the p38γ mitogen-activated protein kinase is located within a mammalian cell. In aspects, the p38γ mitogen-activated protein kinase is located within a human cell. In aspects, the p38γ mitogen-activated protein kinase is located outside a cell. The contacting may be performed in vitro. The contacting may be performed in vivo. In aspects, the ribonucleic acid comprises SEQ ID NO:1 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:2 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:3 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:4 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:5 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:6 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:7 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:8 or a homolog thereof.

Provided herein are methods of reducing or suppressing expression of p38γ MAP kinase in a cell by contacting the cell with a ribonucleic acid described herein (e.g., SEQ ID NO:1, SEQ ID NO:3, or a homolog thereof). The contacting may be performed in vitro. The contacting may be performed in vivo. In aspects, the p38γ MAP kinase is in a mammalian cell. In aspects, the p38γ MAP kinase is in a human cell. In aspects, the ribonucleic acid comprises SEQ ID NO:1 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:2 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:3 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:4 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:5 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:6 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:7 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:8 or a homolog thereof.

Provided herein are methods of suppressing proliferation of a cancer cell by contacting the cancer cell with an effective amount of a p38γ kinase inhibitor described herein (e.g., SEQ ID NO:1, SEQ ID NO:3, or a homolog thereof). In aspects, the cancer cell overexpresses p38γ MAP kinase. In aspects, the cancer cell is a breast cancer cell, a triple negative breast cancer cell, a prostate cancer cell, a colon cancer cell, an ovarian cancer cell, a lymphoma cancer cell, a cutaneous T-cell lymphoma cell, a bladder cancer cell, a lung cancer cell, a thyroid cancer cell, or a head and neck squamous carcinoma cell. In aspects, the p38γ kinase inhibitor is a ribonucleic acid. In aspects, the ribonucleic acid comprises SEQ ID NO:1 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:2 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:3 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:4 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:5 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:6 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:7 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:8 or a homolog thereof. In aspects, the method further comprises administering an effective amount of a second anti-cancer agent.

Provided herein is a method of treating cancer in a subject in need thereof by administering to the subject an effective amount of a p38γ kinase inhibitor described herein (e.g., SEQ ID NO:1, SEQ ID NO:3, or a homolog thereof). In aspects, the cancer overexpresses p38γ MAP kinase. In aspects, the cancer is lymphoma, cutaneous T-cell lymphoma, breast cancer, triple negative breast cancer, prostate cancer, colon cancer, ovarian cancer, bladder cancer, lung cancer, thyroid cancer, or head and neck squamous cell carcinoma. In aspects, the p38γ kinase inhibitor is a ribonucleic acid. In aspects, the ribonucleic acid comprises SEQ ID NO:1 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:2 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:3 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:4 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:5 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:6 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:7 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:8 or a homolog thereof. In aspects, the method further comprises administering an effective amount of a second anti-cancer agent.

Provided herein is a method of treating breast cancer in a subject in need thereof by administering to the subject an effective amount of a p38γ kinase inhibitor described herein (e.g., SEQ ID NO:1, SEQ ID NO:3, or a homolog thereof). In aspects, the p38γ kinase inhibitor is a ribonucleic acid. In aspects, the ribonucleic acid comprises SEQ ID NO:1 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:2 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:3 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:4 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:5 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:6 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:7 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:8 or a homolog thereof. In aspects, the breast cancer overexpresses p38γ MAP kinase. In aspects, the breast cancer is triple negative breast cancer. In aspects, the triple negative breast cancer overexpresses p38γ MAP kinase. In aspects, the method further comprises administering an effective amount of a second anti-cancer agent.

Provided herein is a method of treating prostate cancer in a subject in need thereof by administering to the subject an effective amount of a p38γ kinase inhibitor described herein (e.g., SEQ ID NO:1, SEQ ID NO:3, or a homolog thereof). In aspects, the prostate cancer overexpresses p38γ MAP kinase. In aspects, the p38γ kinase inhibitor is a ribonucleic acid. In aspects, the ribonucleic acid comprises SEQ ID NO:1 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:2 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:3 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:4 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:5 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:6 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:7 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:8 or a homolog thereof. In aspects, the method further comprises administering an effective amount of a second anti-cancer agent.

Provided herein is a method of treating colon cancer in a subject in need thereof by administering to the subject an effective amount of a p38γ kinase inhibitor described herein (e.g., SEQ ID NO:1, SEQ ID NO:3, or a homolog thereof). In aspects, the colon cancer overexpresses p38γ MAP kinase. In aspects, the p38γ kinase inhibitor is a ribonucleic acid. In aspects, the ribonucleic acid comprises SEQ ID NO:1 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:2 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:3 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:4 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:5 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:6 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:7 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:8 or a homolog thereof. In aspects, the method further comprises administering an effective amount of a second anti-cancer agent.

Provided herein is a method of treating ovarian cancer in a subject in need thereof by administering to the subject an effective amount of a p38γ kinase inhibitor described herein (e.g., SEQ ID NO:1, SEQ ID NO:3, or a homolog thereof). In aspects, the ovarian cancer overexpresses p38γ MAP kinase. In aspects, the p38γ kinase inhibitor is a ribonucleic acid. In aspects, the ribonucleic acid comprises SEQ ID NO:1 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:2 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:3 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:4 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:5 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:6 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:7 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:8 or a homolog thereof. In aspects, the method further comprises administering an effective amount of a second anti-cancer agent.

Provided herein is a method of treating lymphoma in a subject in need thereof by administering to the subject an effective amount of a p38γ kinase inhibitor described herein (e.g., SEQ ID NO:1, SEQ ID NO:3, or a homolog thereof). In aspects, the lymphoma overexpresses p38γ MAP kinase. In aspects, the p38γ kinase inhibitor is a ribonucleic acid. In aspects, the ribonucleic acid comprises SEQ ID NO:1 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:2 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:3 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:4 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:5 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:6 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:7 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:8 or a homolog thereof. In aspects, the method further comprises administering an effective amount of a second anti-cancer agent.

Provided herein is a method of treating a cutaneous T-cell lymphoma (CTCL) in a subject in need thereof by administering to the subject an effective amount of a p38γ kinase inhibitor described herein (e.g., SEQ ID NO:1, SEQ ID NO:3, or a homolog thereof). In aspects, the cutaneous T-cell lymphoma overexpresses p38γ MAP kinase. In aspects, the p38γ kinase inhibitor is a ribonucleic acid. In aspects, the ribonucleic acid comprises SEQ ID NO:1 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:2 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:3 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:4 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:5 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:6 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:7 or a homolog thereof. In aspects, the ribonucleic acid comprises SEQ ID NO:8 or a homolog thereof. In aspects, the method further comprises administering an effective amount of a second anti-cancer agent.

In aspects, the methods of treating cancer (e.g., breast cancer, triple negative breast cancer, prostate cancer, colon cancer, ovarian cancer, lymphoma, cutaneous T-cell lymphoma, bladder cancer, lung cancer, thyroid cancer, head and neck squamous cell carcinoma, or any cancer that overexpresses p38γ MAP kinase inhibitor described herein) or suppressing proliferation of a cancer cell further comprise administering to the subject an effective amount of a histone deacetylase (HDAC) inhibitor (HDACi). Non-limiting examples of HDACi include the compound having the following structure:

EXAMPLES

The following examples are for purposes of illustration only and are not intended to limit the spirit or scope of the claims.

Protein based systemic evaluation of ligands by exponential enrichment (SELEX) was used to select anti-p38γ RNA oligonucleotides. The target proteins used in SELEX are phosphorylated p38γ comprising Tyr-182 and Thr-185, as shown by the SDS-Page and Western Blot inFIGS. 1A and 1B, respectively. To identify oligonucleotides (e.g., ribonucleic acids or aptamers) that specifically recognize phosphorylated p38γ, non-phosphorylated p38γ was used for five rounds of the SELEX negative protein selection. The selection procedures are depicted inFIG. 1C. The sequence of each RNA aptamer clone, high throughput deep sequencing was performed through amplicon sequencing, which is a method well known in the art. After 17,996,683 reads in total in deep sequencing, the enrichment was confirmed. By combining analytical methods (enrichment, structure analysis, common motif analysis), p38γ specific aptamer of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, and SEQ ID NO:7 were selected. The secondary structures SEQ ID NO:1 and SEQ ID NO:3 are depicted inFIGS. 2 and 3, respectively, as predicted by NUPACK. In SEQ ID NOS:1-8, each U and each C is a 2F′-modified pyrimidine.

A luminescent kinase activity inhibition assay was conducted utilizing aptamers of SEQ ID NO:1 (P38-Y1), SEQ ID NO:3 (P38-Y2), SEQ ID NO:5 (P38-Y3), SEQ ID NO:7 (P38-Y7), SEQ ID NO:9 (IRRE-1), and SEQ ID NO:10 (IRRE-2). To determine inhibition of kinase activity, human recombinant p38γ proteins and ADP-Glo kits was purchased Promega. The p38 kinase was preincubated with 500 ng of the anti-p38γ RNA aptamers (e.g., P38Y-1, P38-Y2, P38-Y3, P38-Y7) for 30 mins before substrates were added, followed by addition of ATP. Then, ADP-Glo reagent was incubated in the mixture at room temperature, followed by incubation of Kinase detection reagent (Promega).

With reference toFIG. 4, SEQ ID NO:1 (P38-Y1) significantly inhibited kinase activity by 50% compared to controls; SEQ ID NO:3 (P38-Y2) significantly inhibited kinase activity by 20% compared to controls; SEQ ID NO:5 (P38-Y3) significantly inhibited kinase activity by 11% compared to controls; and SEQ ID NO:7 (P38-Y3) significantly inhibited kinase activity by 18% compared to controls. The controls are SEQ ID NOS:9-10.

Informal Sequence Listing