lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): C=C1[C@@H](O)[C@@H]2O[C@]3(CC[C@H](/C=C/[C@H](C)[C@@H]4CC(C)=C[C@@]5(OC(C[C@@](C)(O)C(=O)O)CC[C@H]5O)O4)O3)CC[C@H]2O[C@@H]1[C@@H](O)C[C@H](C)[C@H]1O[C@@]2(CCCCO2)CC[C@H]1C
InChIKey: QNDVLZJODHBUFM-MBHLHSRSSA-N
Target: Serine/threonine-protein phosphatase 6 catalytic subunit (SINGLE PROTEIN), Homo sapiens
UniProt: O00743
Assay: Inhibition of PP6 (unknown origin)
Measurement: IC50 = 1 nM (pChEMBL 9)
Descriptors: MW 805.02, ALogP 5.21, HBA 12, HBD 5, PSA 182.83, QED 0.18
Compound (SMILES): C=CC(=O)Nc1cc(Nc2ncc(C(=O)OCC)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
InChIKey: FCZMHSXKERLEIN-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: ASV & NPG EGFR Exon 20 Insertion Mutations: A compound's ability in selectively inhibiting EGFR exon 20 insertion mutations can be assessed using Ba/F3 cells, a murine pro-B cell line, which have been transduced with EGFR exon 20 insertions. An expression vector, pLVX-IRES puro (Clontech) coding for human EGFR exon 20 insertions NPG (H773_V774insNPG) or ASV (V769_D770insASV), was transfected into HEK293 cells by the Trans-Lentiviral ORF Packaging System (Thermo Scientific), to produce virus encoding EGFR exon 20 insertions. Ba/F3 (DSMZ) cells maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum, 200 μM L-glutamine/200 μg/mL penicillin/200 μg/mL streptomycin (Life Technology) and 10 ng/mL IL-3 (R&D system), were infected by EGFR Exon20 virus and subsequently selected by puromycin (Life Technology) selection and IL-3 depletion. Ba/F3 cells expressing EGFR exon 20 insertions (named Ba/F3-EGFR-Exon20-NPG or Ba/F3-EGFR-Exon20-ASV) can proliferate in the absence of IL-3. The anti-proliferative activity of compounds were determined as follows: BaF3-EGFR-Exon20 cells (NPG or ASV) seeded in 96 well plates (2500 cells/well) were treated with test compound (dissolved in DMSO) at a series of concentrations (4-fold dilution, top concentration: 10,000 nM). The plates were incubated for 72 h in a 37° C. incubator with 5% CO2, and the number of viable cells in each well were measured indirectly by CellTiter 96® Aqueous One Solution Cell Proliferation Assay (Promega) This assay is a colorimetric method for determining the number of viable cells through measurement of their metabolic activity by detection of enzymatic conversion of tetrazolium salts into blue formazan derivatives. Reagent (20 μL) was added into each well, and the plates were returned to the incubator for 2 h. The absorbance in each well was then measured at 490 nm using an Envision plate reader (Perkin Elmer). IC50 values were calculated by determining the concentration of compound required to decrease the MTS signal by 50% comparing to the DMSO control in best-fit curves using Microsoft XLfit software or Accelrys Pipeline Pilot.
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 571.68, ALogP 4.69, HBA 10, HBD 2, PSA 113.85, QED 0.18
Compound (SMILES): N#Cc1cc(C(=O)Nc2ccc3c(c2)S(=O)(=O)C=C3)sc1Sc1c(Cl)cncc1Cl
InChIKey: QYKHTZFZLQQUBF-UHFFFAOYSA-N
Target: Ubiquitin carboxyl-terminal hydrolase 47 (SINGLE PROTEIN), Homo sapiens
UniProt: Q96K76
Assay: Inhibition of human USP47 using Ub-EKL as substrate by SDS-PAGE assay
Measurement: EC50 = 5100 nM (pChEMBL 5.289999961853027)
Descriptors: MW 494.41, ALogP 5.48, HBA 7, HBD 1, PSA 99.92, QED 0.52
Compound (SMILES): COc1cc(N2CCC(N(C)C)CC2)ccc1Nc1ncc(Cl)c(Nc2cccc(B(O)O)c2)n1
InChIKey: HNUKDWWDAQPXIM-UHFFFAOYSA-N
Target: ALK tyrosine kinase receptor (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UM73
Assay: Inhibition of N-terminal GST-tagged human ALK cytoplasmic domain (1058 to 1620 residues) C1156Y mutant expressed in baculovirus-infected Sf21 cells using LANCE Ultra ULight-PolyGT substrate incubated for 2 hrs by TR-FRET assay
Measurement: IC50 = 16.9 nM (pChEMBL 7.769999980926514)
Descriptors: MW 496.81
Compound (SMILES): O=C(Cc1ccc(-c2n[nH]c(=O)c3ccccc23)cc1)N1CCc2ccccc21
InChIKey: COYVFENBIAJDFY-UHFFFAOYSA-N
Target: Rho-associated protein kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O75116
Assay: Inhibition of ROCK2 (unknown origin)
Measurement: IC50 = 7 nM (pChEMBL 8.149999618530273)
Descriptors: MW 381.44, ALogP 3.72, HBA 3, HBD 1, PSA 66.06, QED 0.59
Compound (SMILES): CCn1ncc2ccc(-c3cc(CO[C@](C)(CC)C(=O)O)nn3-c3ccccc3N3CCCC3)cc21
InChIKey: AYMDCHYRSVUUBL-MUUNZHRXSA-N
Target: Monocarboxylate transporter 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P53985
Assay: MCT1-Mediated Lactate Transport in BT20 Breast Cancer Cells: MCT1 activity may be measured using BT-20 breast cancer cells that express high native levels of MCT1, but do not express MCT4 and are known to those with skill in the art. Preparation of BCECF loaded cells are as described for Assay 1. Lactate transport assay is as described for Assay 1, except 10 mM L-lactate (rather than 50 mM) is added.
Measurement: IC50 = 36000 nM (pChEMBL 4.440000057220459)
Descriptors: MW 487.6, ALogP 5.28, HBA 7, HBD 1, PSA 85.41, QED 0.35
Compound (SMILES): COc1cc(CCc2ccccc2)c(C(=O)O)c(O)c1C/C=C(\C)CC=C(C)C
InChIKey: WNQYHTVUADEJHB-LDADJPATSA-N
Target: Peroxisome proliferator-activated receptor gamma (SINGLE PROTEIN), Homo sapiens
UniProt: P37231
Assay: Binding affinity to PPARgamma (unknown origin)
Measurement: Ki = 19 nM (pChEMBL 7.71999979019165)
Descriptors: MW 394.51, ALogP 5.73, HBA 3, HBD 2, PSA 66.76, QED 0.53
Compound (SMILES): Cc1cc(OCc2nc(N)nc(NCCc3cc(F)ccc3F)n2)cc(N2CCCC2=O)c1
InChIKey: IPUBDECQGVKZOD-UHFFFAOYSA-N
Target: Free fatty acid receptor 4 (SINGLE PROTEIN), Homo sapiens
UniProt: Q5NUL3
Assay: Agonist activity at N-terminal FLAG tagged human FFAR4 transfected in African green monkey COS-7 cells assessed as accumulation of inositol phosphate incubated for 90 mins by TopCount NXT counter based analysis
Measurement: EC50 = 5000 nM (pChEMBL 5.300000190734863)
Descriptors: MW 454.48, ALogP 3.4, HBA 7, HBD 2, PSA 106.26, QED 0.54
Compound (SMILES): O=C(Nc1cnccc1-c1ccc(F)cc1C(F)(F)F)c1ccnc(NC(=O)C2CC2)c1
InChIKey: COJODIOMIPYEGM-UHFFFAOYSA-N
Target: Glycogen synthase kinase-3 alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P49840
Assay: Inhibition of GST tagged GSK-3alpha (unknown origin) incubated for 1 hrs by HTRF assay
Measurement: IC50 = 0.17 nM (pChEMBL 9.770000457763672)
Descriptors: MW 444.39, ALogP 4.9, HBA 4, HBD 2, PSA 83.98, QED 0.55
Compound (SMILES): O=C(O)c1ccnc(NCc2cccc(F)c2)c1
InChIKey: YFUUKCJIHIACCK-UHFFFAOYSA-N
Target: Lysine-specific demethylase 5A (SINGLE PROTEIN), Homo sapiens
UniProt: P29375
Assay: Inhibition of N-terminal his6-tagged human KDM5A (1 to 797 residues) expressed in sf9 insect cells incubated for 20 mins by Alphascreen assay
Measurement: IC50 = 100 nM (pChEMBL 7)
Descriptors: MW 246.24, ALogP 2.53, HBA 3, HBD 2, PSA 62.22, QED 0.87
Compound (SMILES): COc1ccc2nc(C(=O)N[C@H]3CC[C@H](C(C)(C)O)CC3)cnc2c1
InChIKey: ZZLWYMYJVFIEIT-JOCQHMNTSA-N
Target: Hematopoietic prostaglandin D synthase (SINGLE PROTEIN), Rattus norvegicus
UniProt: O35543
Assay: Inhibition of H-PGDS in rat RBL cells assessed as reduction in A23187-induced PGD2 production pretreated for 30 mins followed by A23187 addition for 30 mins by RapidFire Mass spectrometry
Measurement: EC50 = 3200 nM (pChEMBL 5.5)
Descriptors: MW 343.43, ALogP 2.7, HBA 5, HBD 2, PSA 84.34, QED 0.89
Compound (SMILES): CC(C)c1sc(-c2csc(Nc3cccc(F)c3)n2)nc1-c1ccccc1
InChIKey: BWTASRQWAGDHFT-UHFFFAOYSA-N
Target: Cytochrome P450 1A1 (SINGLE PROTEIN), Homo sapiens
UniProt: P04798
Assay: Inhibition of recombinant human CYP1A1 using 7-ethyl-0-resorufin as substrate incubated for 30 mins in presence of NADPH by EROD assay
Measurement: IC50 = 7118 nM (pChEMBL 5.150000095367432)
Descriptors: MW 395.53, ALogP 6.94, HBA 5, HBD 1, PSA 37.81, QED 0.4
Compound (SMILES): CN(CC(=O)NC1CCCCC1)C(=O)CCCN1CCN(c2cccc(Cl)c2Cl)CC1
InChIKey: ZQUYISBPDUWNLC-UHFFFAOYSA-N
Target: D(3) dopamine receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P35462
Assay: Partial agonist activity at human D3 receptor expressed in HEK293T cells assessed as inhibition of forskolin-induced cAMP production incubated for 1 hr by HTRF analysis
Measurement: IC50 = 12302.69 nM (pChEMBL 4.909999847412109)
Descriptors: MW 469.46, ALogP 3.8, HBA 4, HBD 1, PSA 55.89, QED 0.63
Compound (SMILES): CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CN(C)CCO)cc1OC
InChIKey: AXVNBVBMOIBASW-IBGZPJMESA-N
Target: Toll-like receptor 8 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NR97
Assay: Agonist activity at human TLR8 in HEK-Blue hTLR8 cells assessed as induction of SEAP production using nitrophenyl phosphate as substrate incubated for 20 hrs by microplate reader analysis
Measurement: EC50 = 2511.89 nM (pChEMBL 5.599999904632568)
Descriptors: MW 431.58, ALogP 2.35, HBA 8, HBD 4, PSA 116.76, QED 0.38
Compound (SMILES): C#CCO[C@@H]1[C@H](C)[C@@H](COC(=O)c2ccc(S(=O)(=O)F)cc2)O[C@H]1n1nc(-c2ccc(C)cc2)c2c(N)ncnc21
InChIKey: VCIZYTQJDGPPDJ-CLQHIKNWSA-N
Target: Tyrosine-protein kinase Yes (SINGLE PROTEIN), Homo sapiens
UniProt: P07947
Assay: Inhibition of YES (unknown origin)
Measurement: IC50 = 1.3 nM (pChEMBL 8.890000343322754)
Descriptors: MW 579.61, ALogP 3.45, HBA 11, HBD 1, PSA 148.52, QED 0.19
Compound (SMILES): C#CCOC(=O)[C@]1(C)CC[C@]2(C)CC[C@]3(C)C4=CC=C5C(=CC(=O)C(OC(=O)N6CCC(N7CCCCC7)CC6)=C5C)[C@]4(C)CC[C@@]3(C)[C@@H]2C1
InChIKey: CGNBJUFJFIYHSW-VZHCALMGSA-N
Target: Caspase-3 (SINGLE PROTEIN), Homo sapiens
UniProt: P42574
Assay: Binding affinity to human recombinant caspase 3 at 0.3125 to 5 uM measured after 400 secs by Surface plasmon resonance method
Measurement: Kd = 3800 nM (pChEMBL 5.420000076293945)
Descriptors: MW 682.95, ALogP 8.32, HBA 6, HBD 0, PSA 76.15, QED 0.22
Compound (SMILES): CC(=O)Oc1cccc(C2CCN(Cc3cn(-c4ccccc4)nn3)CC2)c1
InChIKey: MYIODXYMHNJTDW-UHFFFAOYSA-N
Target: Sigma non-opioid intracellular receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q99720
Assay: Displacement of [3H](+)-pentazocine from human sigma 1 receptor expressed in HEK293 cells membrane incubated for 120 mins by MicroBeta scintillation counter assay
Measurement: Ki < 100 nM (pChEMBL 7)
Descriptors: MW 376.46, ALogP 3.57, HBA 6, HBD 0, PSA 60.25, QED 0.5
Compound (SMILES): COc1ccc(OC)c(-n2nnc(C(=O)Nc3cc(C(C)(C)C)ccc3NC(=O)OC(C)(C)C)c2C)c1
InChIKey: CUNUZLYVMVYOSX-UHFFFAOYSA-N
Target: Nuclear receptor subfamily 1 group I member 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O75469
Assay: Agonist activity at human PXR in human HepG2 cells co-expressing luciferase gene under control of CYP3A4 promoter assessed as transcriptional activation incubated for 24 hrs by luminescence based analysis
Measurement: EC50 = 150 nM (pChEMBL 6.820000171661377)
Descriptors: MW 509.61, ALogP 5.49, HBA 8, HBD 2, PSA 116.6, QED 0.45
Compound (SMILES): Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N(CC(C)C)S(=O)(=O)c1ccc2c(c1)C(O)CC(C1CCOCC1)O2
InChIKey: VZLWGHJFVQLRMI-UHFFFAOYSA-N
Target: Nuclear receptor ROR-gamma (SINGLE PROTEIN), Homo sapiens
UniProt: P51449
Assay: Inhibition of RORgammat in human Jurkat cells assessed as inhibition of RORgammat transcriptional activity incubated for 10 mins by luciferase reporter gene assay
Measurement: IC50 = 39 nM (pChEMBL 7.409999847412109)
Descriptors: MW 625.63, ALogP 5.77, HBA 6, HBD 2, PSA 96.3, QED 0.38
Compound (SMILES): CCS(=O)(=O)c1ccc(CC(=O)Nc2ccc(-c3nc4ccc(C(F)(F)F)cc4n3[C@H](C)c3ccc(F)cc3)cc2)cc1
InChIKey: KPMTUCCYXWPTAN-HXUWFJFHSA-N
Target: Oxysterols receptor LXR-alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q13133
Assay: Inverse agonist activity at human GAL4-fused LXRalpha LBD transfected in 293T cell measured after 24 hrs by dual luciferase assay
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 609.65, ALogP 7.45, HBA 5, HBD 1, PSA 81.06, QED 0.19
Compound (SMILES): CCOc1ccc(C(C)(C)C)cc1NC(=O)c1nnn(-c2cc(OC)ccc2OC)c1C
InChIKey: PCPOIPOIDJLKPQ-UHFFFAOYSA-N
Target: Nuclear receptor subfamily 1 group I member 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O75469
Assay: Antagonist activity at human PXR in human HepG2 cells co-expressing luciferase gene under control of CYP3A4 promoter assessed as inhibition in rifampicin-induced receptor activation incubated for 24 hrs by luminescence based analysis
Measurement: IC50 = 460 nM (pChEMBL 6.340000152587891)
Descriptors: MW 438.53, ALogP 4.54, HBA 7, HBD 1, PSA 87.5, QED 0.58
Compound (SMILES): Cc1ccc(-c2noc(-c3cccc(OCC4CCN(Cc5ccccc5F)CC4)c3)n2)cn1
InChIKey: DSACCWNHUDYWJF-UHFFFAOYSA-N
Target: Acetylcholinesterase (SINGLE PROTEIN), Homo sapiens
UniProt: P22303
Assay: Inhibition of human AChE using ATC and BTC iodide as substrate preincubated for 5 mins followed by substrate addition and measured after 2 mins by DTNB reagent based assay
Measurement: IC50 = 290 nM (pChEMBL 6.539999961853027)
Descriptors: MW 458.54, ALogP 5.54, HBA 6, HBD 0, PSA 64.28, QED 0.36
Compound (SMILES): CCOc1ccccc1-c1ccc(-c2nc3cnccc3c(NC(C(N)=O)C3CC3)c2C#N)cc1
InChIKey: HYSPHLALGJESRU-UHFFFAOYSA-N
Target: Phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P48426
Assay: Inhibition of human PIP4K2A in human THP-1 cells assessed as increase in Akt phosphorylation at Ser473 residue incubated for 2 hrs by HTRF assay
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 463.54, ALogP 4.91, HBA 6, HBD 2, PSA 113.92, QED 0.38
Compound (SMILES): O=C(c1ccco1)N1CCCc2cc(N(S(=O)(=O)c3ccc(Cl)cc3)S(=O)(=O)c3ccc(Cl)cc3)ccc21
InChIKey: QDXZEENUKMJAQV-UHFFFAOYSA-N
Target: Glucocorticoid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P04150
Assay: Modulation of glucocorticoid receptor (unknown origin) transfected in human HeLa cells assessed as transrepression by measuring inhibition of PMA-induced AP-1 signalling incubated for 18 hrs by dual-luciferase reporter based assay
Measurement: IC50 = 3960 nM (pChEMBL 5.400000095367432)
Descriptors: MW 591.49, ALogP 5.76, HBA 6, HBD 0, PSA 104.97, QED 0.28
Compound (SMILES): COc1cc(C)c(Cl)cc1S(=O)(=O)Nc1ccc2c(c1)CCCN2C(=O)c1ccc(Cl)cc1
InChIKey: ITHYFWFKBVRNSO-UHFFFAOYSA-N
Target: Glucocorticoid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P04150
Assay: Modulation of glucocorticoid receptor (unknown origin) transfected in human HeLa cells assessed as transrepression by measuring inhibition of PMA-induced AP-1 signalling incubated for 18 hrs by dual-luciferase reporter based assay
Measurement: IC50 = 1810 nM (pChEMBL 5.739999771118164)
Descriptors: MW 505.42, ALogP 5.7, HBA 4, HBD 1, PSA 75.71, QED 0.48
Compound (SMILES): CC(C)Oc1ccc2c(c1)OC1(CCN(c3ccc(S(N)(=O)=O)cc3[N+](=O)[O-])CC1)CC2=O
InChIKey: WMQZROFIRWJGMY-UHFFFAOYSA-N
Target: Carbonic anhydrase 7 (SINGLE PROTEIN), Homo sapiens
UniProt: P43166
Assay: Binding affinity to human CA7 assessed as inhibition constant
Measurement: Ki = 0.35 nM (pChEMBL 9.460000038146973)
Descriptors: MW 475.52, ALogP 3.03, HBA 8, HBD 1, PSA 142.07, QED 0.51
Compound (SMILES): O=c1c2ccccc2[se]n1Cc1ccco1
InChIKey: QZJDTYZIHCOMMO-UHFFFAOYSA-N
Target: Replicase polyprotein 1ab (SINGLE PROTEIN), Severe acute respiratory syndrome coronavirus 2
UniProt: P0DTD1
Assay: Inhibition of N-terminal SARS-CoV-2 Main protease expressed in Escherichia coli BL21 (DE3) by using MCA-AVLQSGFR-Lys (Dnp)-Lys-NH as fluorogenic substrate by FRET assay
Measurement: IC50 = 70 nM (pChEMBL 7.159999847412109)
Descriptors: MW 278.17
Compound (SMILES): Cn1nccc1-n1c([C@@H]2CSCN2c2ncnc3[nH]cnc23)nc2cccc(Cl)c2c1=O
InChIKey: QYNRNMIXOUFJAP-ZDUSSCGKSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Inhibition of PI3Kgamma (unknown origin) incubated for 90 mins by [gamma-33P]-ATP based scintillation counting method
Measurement: IC50 = 420 nM (pChEMBL 6.380000114440918)
Descriptors: MW 465.93, ALogP 2.69, HBA 10, HBD 1, PSA 110.41, QED 0.43
Compound (SMILES): Cc1cc(/N=N/c2cc(S(=O)(=O)O)c3ccccc3c2N)ccc1-c1ccc(/N=N/c2cc(S(=O)(=O)O)c3ccccc3c2N)cc1C.[NaH]
InChIKey: PTJLLMBFBMRJKP-DVDDBBOFSA-N
Target: Sentrin-specific protease 3 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9H4L4
Assay: Inhibition of SENP3 (unknown origin)
Measurement: IC50 = 4800 nM (pChEMBL 5.320000171661377)
Descriptors: MW 680.77, ALogP 8.77, HBA 10, HBD 4, PSA 210.22, QED 0.07
Compound (SMILES): Cc1cc(Oc2ccc(S(=O)(=O)N(CC(C)C)c3ccc(O)c(C(=O)O)c3)cc2)cc(C)c1Cl
InChIKey: QVDQXTZYQIUQHH-UHFFFAOYSA-N
Target: Bcl-2-like protein 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q07817
Assay: fluorescence polarization competition assay (FPCA): Molecular modeling and SILCS functional group affinity mapping (FragMaps) of the Mcl-1 binding site indicated that the carboxylic acid of designed molecule 3a (FIG. 1C) would occupy an energetically favorable region, associated with a salt bridge interaction with R263 of the Mcl-1 binding site, while the ring of the naphthyl core would bind in the p3 pocket demarcated by a favorable non-polar FragMap. The aniline was directed into the hydrophobic p2 pocket, which is also demarcated by a nonpolar FragMap. With the molecular modeling data in hand, compound 3a was then synthesized according to Scheme 1-2.Briefly, commercially available 1-hydroxy-2-naphthoic acid (4) was regioselectively 4-chlorosulfonylated to yield 5, which was isolated by pouring over ice and used without further purification. Sulfonyl chloride 5 was next reacted with 4-bromoaniline to furnish the target molecule 3a in excellent overall yield (83%). Evaluation of 3a in a fluorescence polarization competition assay (FPCA) indicated that it disrupted the Mcl-1-Bak-BH3 PPI with an IC50 of 10.9 μM, corresponding to a Ki of 2.76 μM. Given the ability of 3a to inhibit Mcl-1, a structure-activity relationship (SAR) study was developed, the results of which are presented in the tables below.
Measurement: Ki = 2905 nM (pChEMBL 5.539999961853027)
Descriptors: MW 504, ALogP 6, HBA 5, HBD 2, PSA 104.14, QED 0.39
Compound (SMILES): Cc1ccc2c(=O)n(Cc3ccccc3)c(SCc3cn(-c4ccc(C(=O)O)cc4)nn3)nc2c1
InChIKey: LNMIYHCOSIHDEA-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR (unknown origin) by ELISA
Measurement: IC50 = 38.8 nM (pChEMBL 7.409999847412109)
Descriptors: MW 483.55, ALogP 4.32, HBA 8, HBD 1, PSA 102.9, QED 0.27
Compound (SMILES): O=C(CCCN1CCN(c2cccc(Cl)c2Cl)CC1)N1C=CN(Cc2ccccc2)C(=O)C1
InChIKey: NKFOMNCXPUBCJT-UHFFFAOYSA-N
Target: D(4) dopamine receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P21917
Assay: Partial agonist activity at human D4 receptor expressed in HEK293T cells assessed as inhibition of forskolin-induced cAMP production incubated for 1 hr by HTRF analysis
Measurement: IC50 = 5754.4 nM (pChEMBL 5.239999771118164)
Descriptors: MW 487.43, ALogP 4.24, HBA 4, HBD 0, PSA 47.1, QED 0.59
Compound (SMILES): Cc1cc(Nc2ncc(Cl)c(Nc3cccc4c3B(O)OC4)n2)c(OC(C)C)cc1C1CCNCC1
InChIKey: WIIZIOIRVCPAGM-UHFFFAOYSA-N
Target: ALK tyrosine kinase receptor (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UM73
Assay: Inhibition of N-terminal GST-tagged human ALK cytoplasmic domain (1058 to 1620 residues) L1196M mutant expressed in baculovirus-infected Sf21 cells using LANCE Ultra ULight-PolyGT substrate incubated for 2 hrs by TR-FRET assay
Measurement: IC50 = 6.6 nM (pChEMBL 8.180000305175781)
Descriptors: MW 507.83
Compound (SMILES): c1cncc(C[C@H]2[C@H](Oc3ccc(-c4ccc5[nH]ccc5c4)cn3)C3CCN2CC3)c1
InChIKey: YGUAOPWRSCDURL-AZGAKELHSA-N
Target: Neuronal acetylcholine receptor; alpha3/beta4 (PROTEIN COMPLEX), Homo sapiens
UniProt: P32297
Assay: Binding affinity to alpha3beta4 nAChR (unknown origin) assessed as dissociation constant
Measurement: Ki = 780 nM (pChEMBL 6.110000133514404)
Descriptors: MW 410.52, ALogP 4.71, HBA 4, HBD 1, PSA 54.04, QED 0.52
Compound (SMILES): CC(C)C(NC(=O)C1CCCC1)C(=O)Nc1nnc(Cc2ccc([N+](=O)[O-])cc2)s1
InChIKey: QZLFYUNOXBTBKP-UHFFFAOYSA-N
Target: Ubiquitin carboxyl-terminal hydrolase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O75604
Assay: Inhibition of human His-tagged USP2 (259 to 605 residues) using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay
Measurement: IC50 > 25000 nM (pChEMBL 4.6020002365112305)
Descriptors: MW 431.52, ALogP 3.31, HBA 7, HBD 2, PSA 127.12, QED 0.49
Compound (SMILES): Fc1cc(Cl)ccc1-c1csc(-c2csc(Nc3ccc(N4CCOCC4)cc3)n2)n1
InChIKey: CSPUPGNBRAIDFV-UHFFFAOYSA-N
Target: Cytochrome P450 1A2 (SINGLE PROTEIN), Homo sapiens
UniProt: P05177
Assay: Inhibition of recombinant human CYP1A2 using 7-ethyl-0-resorufin as substrate incubated for 30 mins in presence of NADPH by EROD assay
Measurement: IC50 = 995.5 nM (pChEMBL 6)
Descriptors: MW 473, ALogP 6.31, HBA 7, HBD 1, PSA 50.28, QED 0.37
Compound (SMILES): Cc1cc(CNCCCCCCC(=O)NO)ccc1F
InChIKey: JUPDVVWNENNSPJ-UHFFFAOYSA-N
Target: Histone deacetylase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: O15379
Assay: Inhibition of human recombinant HDAC3 expressed in baculovirus by using Boc-L-Lys(Ac)-AMC as substrate measured after 24 hrs by fluorescence based analysis
Measurement: IC50 = 190 nM (pChEMBL 6.71999979019165)
Descriptors: MW 282.36, ALogP 2.68, HBA 3, HBD 3, PSA 61.36, QED 0.37
Compound (SMILES): COC(=O)C1(c2ccccc2)CC1CN1CC[C@@]2(C)c3cc(O)ccc3C[C@H]1[C@H]2C
InChIKey: ZQZLNUMNWMAXIZ-BNERBJGHSA-N
Target: Delta-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41143
Assay: Displacement of [3H]-Diprenorphine from DOR receptor (unknown origin) assessed as inhibition constant
Measurement: Ki > 1000 nM (pChEMBL 6)
Descriptors: MW 405.54, ALogP 4.05, HBA 4, HBD 1, PSA 49.77, QED 0.78
Compound (SMILES): C=CC(=O)N1CCC(C2CCNc3c(C(N)=O)c(-c4cc(Cl)c(Cl)c(Cl)c4)nn32)CC1
InChIKey: LXOADFXFUMUSSE-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Tec (SINGLE PROTEIN), Homo sapiens
UniProt: P42680
Assay: Inhibition of TEC (unknown origin) preincubated for 1 hrs followed by substrate addition and measured after 1 hrs in the presence of ATP at Km concentration by TR-FRET assay
Measurement: IC50 = 189 nM (pChEMBL 6.71999979019165)
Descriptors: MW 482.8, ALogP 4.39, HBA 5, HBD 2, PSA 93.25, QED 0.5
Compound (SMILES): C=CC(=O)N1CCC(C2CCNc3c(C(N)=O)c(-c4cc(OC)c(C)c(OC)c4)nn32)CC1
InChIKey: ZFDGMDVYMNWICG-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Tec (SINGLE PROTEIN), Homo sapiens
UniProt: P42680
Assay: Inhibition of TEC (unknown origin) preincubated for 1 hrs followed by substrate addition and measured after 1 hrs in the presence of ATP at Km concentration by TR-FRET assay
Measurement: IC50 = 216 nM (pChEMBL 6.670000076293945)
Descriptors: MW 453.54, ALogP 2.76, HBA 7, HBD 2, PSA 111.71, QED 0.65
Compound (SMILES): CCOC(=O)c1ncc2[nH]c3ccccc3c2c1COC
InChIKey: IUHKSTINHDUYRO-UHFFFAOYSA-N
Target: Gamma-aminobutyric acid receptor subunit alpha-3 (SINGLE PROTEIN), Homo sapiens
UniProt: P34903
Assay: Binding affinity to human recombinant GABAA alpha3 receptor assessed as inhibition constant incubated for 1 hrs by liquid scintillation counting analysis
Measurement: Ki = 5 nM (pChEMBL 8.300000190734863)
Descriptors: MW 284.31, ALogP 3.04, HBA 4, HBD 1, PSA 64.21, QED 0.75
Compound (SMILES): CC(C)(C)NC(=O)C1C(=O)NCCN1C(=O)CCCN1CCN(c2cccc(Cl)c2Cl)CC1
InChIKey: APQWXABKECJSIH-UHFFFAOYSA-N
Target: D(4) dopamine receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P21917
Assay: Partial agonist activity at human D4 receptor expressed in HEK293T cells assessed as inhibition of forskolin-induced cAMP production incubated for 1 hr by HTRF analysis
Measurement: IC50 = 6606.93 nM (pChEMBL 5.179999828338623)
Descriptors: MW 498.46, ALogP 2.14, HBA 5, HBD 2, PSA 84.99, QED 0.59
Compound (SMILES): CCOc1cc(C)nc2c(C#N)c(Nc3cc(OC)ccn3)nn12
InChIKey: KYOSHYZHJHZGQB-UHFFFAOYSA-N
Target: Phospholipase A2, membrane associated (SINGLE PROTEIN), Homo sapiens
UniProt: P14555
Assay: Inhibition of recombinant human sPLA2-V
Measurement: IC50 = 1700 nM (pChEMBL 5.769999980926514)
Descriptors: MW 324.34, ALogP 2.46, HBA 8, HBD 1, PSA 97.36, QED 0.77
Compound (SMILES): CCc1sc(-c2csc(Nc3ccc(N4CCOCC4)cc3)n2)nc1-c1ccncc1
InChIKey: NPDJSUQIELHWDQ-UHFFFAOYSA-N
Target: Cytochrome P450 1A2 (SINGLE PROTEIN), Homo sapiens
UniProt: P05177
Assay: Inhibition of recombinant human CYP1A2 using 7-ethyl-0-resorufin as substrate incubated for 30 mins in presence of NADPH by EROD assay
Measurement: IC50 = 3453 nM (pChEMBL 5.460000038146973)
Descriptors: MW 449.61, ALogP 5.47, HBA 8, HBD 1, PSA 63.17, QED 0.42
Compound (SMILES): CNCCNCc1cccc(-c2nc(Nc3ccccc3)c(C)c(-c3c(C)noc3C)n2)c1
InChIKey: DVIUIRPCVXVFSX-UHFFFAOYSA-N
Target: Histone-arginine methyltransferase CARM1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q86X55
Assay: Inhibition of human CARM1 (140 to 480 residues) incubated for 15 mins measured after 60 min by AlphaLISA assay
Measurement: IC50 = 3.7 nM (pChEMBL 8.430000305175781)
Descriptors: MW 442.57, ALogP 4.78, HBA 7, HBD 3, PSA 87.9, QED 0.32
Compound (SMILES): CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
InChIKey: CVBFLZPOJZBXKW-UHFFFAOYSA-N
Target: Wee1-like protein kinase (SINGLE PROTEIN), Homo sapiens
UniProt: P30291
Assay: Inhibition of WEE1 in human U2OS cells incubated for 1 hr by mesoscale discovery assay
Measurement: IC50 = 148 nM (pChEMBL 6.829999923706055)
Descriptors: MW 509.44, ALogP 5.28, HBA 7, HBD 1, PSA 66.29, QED 0.4
Compound (SMILES): CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)/C=N/OCc1ccc(S(N)(=O)=O)cc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(C)C)[C@@H](C)O
InChIKey: OVYKBARNSMGXPZ-OLTRRQNTSA-N
Target: Carbonic anhydrase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00915
Assay: Inhibition of human carbonic anhydrase 1 assessed as inhibition constant
Measurement: Ki = 104.7 nM (pChEMBL 6.980000019073486)
Descriptors: MW 1179.32
Compound (SMILES): CCCCNNC(=O)c1ccc(F)cc1
InChIKey: YRLLWXIGAGZKFP-UHFFFAOYSA-N
Target: Histone deacetylase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q92769
Assay: HDAC Inhibition: These SAR data indicate that a tripartite structure of this scaffold with a central C(O)NHNH unit flanked by a phenyl group and a short aliphatic chain increases HDAC inhibition. As for the phenyl group, the presence of a relatively bulky substituent at the para position relative to the carbonyl group also affords potent HDAC inhibitors.
Measurement: IC50 = 15100 nM (pChEMBL 4.820000171661377)
Descriptors: MW 210.25, ALogP 1.86, HBA 2, HBD 2, PSA 41.13, QED 0.58
Compound (SMILES): Cc1onc(-c2ccccc2)c1C(=O)NCCCCCNC(=O)C(C)(C)S
InChIKey: XJTVLNNVIZUFGI-UHFFFAOYSA-N
Target: Histone deacetylase 3/Nuclear receptor corepressor 2 (HDAC3/NCoR2) (PROTEIN COMPLEX), Homo sapiens
UniProt: Q9Y618
Assay: Inhibition of human recombinant HDAC3/NCOR2 expressed in baculovirus infected Sf9 cells using RHKKAc as substrate preincubated for 5 to 10 mins followed by substrate addition and measured after 2 hrs by fluorescence based analysis
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 389.52, ALogP 3.37, HBA 5, HBD 3, PSA 84.23, QED 0.45
Compound (SMILES): O=C(OC[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc(Br)cc1)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1
InChIKey: ULQDLVLVQKVZBG-GGXMVOPNSA-N
Target: Cathepsin B (SINGLE PROTEIN), Homo sapiens
UniProt: P07858
Assay: Inhibition of human cathepsin B
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 657.61, ALogP 4.47, HBA 6, HBD 2, PSA 118.64, QED 0.21
Compound (SMILES): COc1cc(OCc2cccc(-c3ccccc3)c2C)cc(OC)c1CCCC1CC(=O)N1
InChIKey: WVWFXRZTHLBYHT-UHFFFAOYSA-N
Target: Programmed cell death 1 ligand 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NZQ7
Assay: Inhibition of human PD-L1 expressed in Escherichia coli BL21 (DE3) incubated for 1 hr by TR-FRET assay
Measurement: IC50 = 22 nM (pChEMBL 7.659999847412109)
Descriptors: MW 445.56, ALogP 5.47, HBA 4, HBD 1, PSA 56.79, QED 0.42
Compound (SMILES): O=C(Nc1cccc(S(=O)(=O)N2CCCCC2)c1)c1cn[nH]c1-c1ccc(Cl)cc1
InChIKey: LIKPCUYPZUOYKD-UHFFFAOYSA-N
Target: Centromere-associated protein E (SINGLE PROTEIN), Homo sapiens
UniProt: Q02224
Assay: Inhibition of recombinant GST-tagged human CENP-E assessed as inhibition of microtubule-stimulated ATPase activity preincubated for 30 mins followed by ATP addition and further incubated for 15 mins by ADP-Glo reagent based assay
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 444.94, ALogP 4.16, HBA 4, HBD 2, PSA 95.16, QED 0.62
Compound (SMILES): COc1ccc(OC)c(-n2nnc(C(=O)Nc3ccc(O)c(C(C)(C)C)c3)c2C)c1
InChIKey: RUHPAZDZYHFFLO-UHFFFAOYSA-N
Target: Nuclear receptor subfamily 1 group I member 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O75469
Assay: Antagonist activity at human PXR in human HepG2 cells co-expressing luciferase gene under control of CYP3A4 promoter assessed as inhibition in rifampicin-induced receptor activation incubated for 24 hrs by luminescence based analysis
Measurement: IC50 = 860 nM (pChEMBL 6.070000171661377)
Descriptors: MW 410.47, ALogP 3.85, HBA 7, HBD 2, PSA 98.5, QED 0.62
Compound (SMILES): Cc1cccc(S(=O)(=O)NC(=O)c2cc(C(=O)O)ccn2)c1
InChIKey: NIRPBGLGHMHJRL-UHFFFAOYSA-N
Target: Alpha-ketoglutarate-dependent dioxygenase alkB homolog 3 (SINGLE PROTEIN), Homo sapiens
UniProt: Q96Q83
Assay: Inhibition of human ALKBH3 expressed in Escherichia coli BL21 (DE3) Rosetta cells
Measurement: IC50 = 11400 nM (pChEMBL 4.940000057220459)
Descriptors: MW 320.33, ALogP 1.21, HBA 5, HBD 2, PSA 113.43, QED 0.87
Compound (SMILES): C=CC(=O)N1CCC(C2CCNc3c(C(N)=O)c(-c4cc(OC)c(Oc5ccccc5)c(OC)c4)nn32)CC1
InChIKey: HEFUQOMXBZIABJ-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Tec (SINGLE PROTEIN), Homo sapiens
UniProt: P42680
Assay: Inhibition of TEC (unknown origin) preincubated for 1 hrs followed by substrate addition and measured after 1 hrs in the presence of ATP at Km concentration by TR-FRET assay
Measurement: IC50 = 59 nM (pChEMBL 7.230000019073486)
Descriptors: MW 531.61, ALogP 4.24, HBA 8, HBD 2, PSA 120.94, QED 0.42
Compound (SMILES): Cc1c(C(=O)NC23CC4CC(CC(C4)C2)C3)nn(CCCCCO)c1-c1ccccc1
InChIKey: FMJXYCCDMAGPLE-UHFFFAOYSA-N
Target: Cannabinoid receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P34972
Assay: Displacement of [3H]-CP55940 from human CB2 receptor expressed in HEK293 cell membrane assessed as inhibition constant incubated for 90 mins by radioligand competition binding assay
Measurement: Ki = 0.08 nM (pChEMBL 10.100000381469727)
Descriptors: MW 421.59, ALogP 4.72, HBA 4, HBD 2, PSA 67.15, QED 0.61
Compound (SMILES): C=CC(=O)Nc1cc(Nc2ncc(C(=O)OC(C)C)c(-c3cn(CC)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
InChIKey: FDTGYJGRULJHQZ-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: EGFR Exon 19 Deletion and Exon 20 T790M Concurrent Mutations: A compound's ability in selectively inhibiting EGFR exon 19 deletion and T790M concurrent mutations can be assessed using Ba/F3 cells, a murine pro-B cell line, which have been transduced with EGFR exon 19 deletion and T790M mutation. An expression vector, pLVX-IRES puro (Clontech) coding for human EGFR E746-A750 deletion and T790M Mutation, was transfected into HEK293 cells by the Trans-Lentiviral ORF Packaging System (Thermo Scientific), to produce virus encoding EGFR exon 19 deletion and T790M mutations. Ba/F3 (DSMZ) cells maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum, 200 μM L-glutamine/200 μg/mL penicillin/200 μg/mL streptomycin (Life Technology) and 10 ng/mL IL-3 (R&D system), were infected by EGFR E746-A750 deletion and T790M Mutation virus and subsequently selected by puromycin (Life Technology) selection and IL-3 depletion. Ba/F3 cells expressing EGFR E746-A750 deletion and T790M Mutation (named Ba/F3-EGFR-Del/T790M) can proliferate in the absence of IL-3. The anti-proliferative activity of compounds was determined as follows: BaF3-EGFR-Del/T790M cells seeded in 96 well plates (2500 cells/well) were treated with test compound (dissolved in DMSO) at a series of concentrations (4-fold dilution, top concentration: 10,000 nM). The plates were incubated for 72 h in a 37° C. incubator with 5% CO2, and the number of viable cells in each well were measured indirectly by CellTiter 96® Aqueous One Solution Cell Proliferation Assay (Promega; this assay is a colorimetric method for determining the number of viable cells through measurement of their metabolic activity by detection of enzymatic conversion of tetrazolium salts into blue formazan derivatives). Reagent (20 μL) was added into each well, and the plates were returned to the incubator for 2 h. The absorbance in each well was then measured at 490 nm using an Envision plate reader (Perkin Elmer). IC50 values were calculated by determining the concentration of compound required to decrease the MTS signal by 50% comparing to the DMSO control in best-fit curves using Microsoft XLfit software or Accelrys Pipeline Pilot.
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 599.74, ALogP 5.56, HBA 10, HBD 2, PSA 113.85, QED 0.15
Compound (SMILES): Cc1cc(Oc2ccc(S(=O)(=O)N(CC(C)C)c3ccc(C(=O)O)c(O)c3)cc2)cc(C)c1Cl
InChIKey: BQOXGDSIGCZKCK-UHFFFAOYSA-N
Target: Bcl-2-like protein 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q07817
Assay: fluorescence polarization competition assay (FPCA): Molecular modeling and SILCS functional group affinity mapping (FragMaps) of the Mcl-1 binding site indicated that the carboxylic acid of designed molecule 3a (FIG. 1C) would occupy an energetically favorable region, associated with a salt bridge interaction with R263 of the Mcl-1 binding site, while the ring of the naphthyl core would bind in the p3 pocket demarcated by a favorable non-polar FragMap. The aniline was directed into the hydrophobic p2 pocket, which is also demarcated by a nonpolar FragMap. With the molecular modeling data in hand, compound 3a was then synthesized according to Scheme 1-2.Briefly, commercially available 1-hydroxy-2-naphthoic acid (4) was regioselectively 4-chlorosulfonylated to yield 5, which was isolated by pouring over ice and used without further purification. Sulfonyl chloride 5 was next reacted with 4-bromoaniline to furnish the target molecule 3a in excellent overall yield (83%). Evaluation of 3a in a fluorescence polarization competition assay (FPCA) indicated that it disrupted the Mcl-1-Bak-BH3 PPI with an IC50 of 10.9 μM, corresponding to a Ki of 2.76 μM. Given the ability of 3a to inhibit Mcl-1, a structure-activity relationship (SAR) study was developed, the results of which are presented in the tables below.
Measurement: Ki = 1629 nM (pChEMBL 5.789999961853027)
Descriptors: MW 504, ALogP 6, HBA 5, HBD 2, PSA 104.14, QED 0.39
Compound (SMILES): O=C(CNc1cc(Cl)cc(Cl)c1)N1CC[C@H]2CCN(c3ncnc4[nH]ccc34)[C@H]2C1
InChIKey: ZJKAMIGVAPQVOU-UGSOOPFHSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 in human liver microsomes using testosterone as substrate measured after 15 mins in the presence of NADPH by LC/MS/MS analysis
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 445.35, ALogP 3.8, HBA 5, HBD 2, PSA 77.15, QED 0.64
Compound (SMILES): C=CC(=O)N1CCC(C2CCNc3c(C(N)=O)c(-c4cc(OC)c5c(C)csc5c4)nn32)CC1
InChIKey: ZDWLIFUKOJCBAL-UHFFFAOYSA-N
Target: Tyrosine-protein kinase Tec (SINGLE PROTEIN), Homo sapiens
UniProt: P42680
Assay: Inhibition of TEC (unknown origin) preincubated for 1 hrs followed by substrate addition and measured after 1 hrs in the presence of ATP at Km concentration by TR-FRET assay
Measurement: IC50 = 22.1 nM (pChEMBL 7.659999847412109)
Descriptors: MW 479.61, ALogP 3.96, HBA 7, HBD 2, PSA 102.48, QED 0.54
Compound (SMILES): CN1CCN(c2ccc(Nc3nccc(-c4cccnc4)n3)cc2C(F)(F)F)CC1
InChIKey: JWOVGKOVFZNPSO-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase PknB (SINGLE PROTEIN), Mycobacterium tuberculosis
UniProt: P9WI81
Assay: Binding affinity to Mycobacterium tuberculosis recombinant N-terminal His-tagged PknB (1 to 331 residues) expressed in Escherichia coli DH5alpha cells by microscale thermophoresis analysis
Measurement: Kd = 61 nM (pChEMBL 7.210000038146973)
Descriptors: MW 414.44, ALogP 4.05, HBA 6, HBD 1, PSA 57.18, QED 0.7
Compound (SMILES): CS(=O)(=O)N1CCC(Nc2ncc3cc(COC4CC4)c(=O)n(C4CCCC4)c3n2)CC1
InChIKey: YAGWJHKKLYYWQN-UHFFFAOYSA-N
Target: CDK6/cyclin D1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24385
Assay: Inhibition of CDK6/cyclin D1 (unknown origin) assessed as reduction in substrate peptide phosphorylation using DYRKtide peptide as substrate preincubated for 12 mins followed by ATP addition and measured for 45 mins by mobility shift assay
Measurement: Ki = 1.44 nM (pChEMBL 8.84000015258789)
Descriptors: MW 461.59, ALogP 2.42, HBA 8, HBD 1, PSA 106.42, QED 0.67
Compound (SMILES): CNc1cc(-c2ccnc(Nc3ccc(N4CCN(C)CC4)c(C(F)(F)F)c3)n2)ccn1
InChIKey: KHBUJYBNSDDNHK-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase PknB (SINGLE PROTEIN), Mycobacterium tuberculosis
UniProt: P9WI81
Assay: Binding affinity to Mycobacterium tuberculosis recombinant N-terminal His-tagged PknB (1 to 331 residues) expressed in Escherichia coli DH5alpha cells by microscale thermophoresis analysis
Measurement: Kd = 920 nM (pChEMBL 6.039999961853027)
Descriptors: MW 443.48, ALogP 4.09, HBA 7, HBD 2, PSA 69.21, QED 0.62
Compound (SMILES): O=C([O-])CNC(=O)c1ccc(S(=O)(=O)N2CCC(c3ccc(Cl)cc3)CC2)cn1.[K+]
InChIKey: DJLPNUNUNPABGA-UHFFFAOYSA-M
Target: Ubiquitin carboxyl-terminal hydrolase 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P45974
Assay: Binding affinity to biotinylated USP5 zinc finger ubiquitin binding domain (171 to 290 residues) (unknown origin) expressed in Escherichia coli incubated for 120 secs by Biolayer Interferometry assay
Measurement: Kd = 3400 nM (pChEMBL 5.46999979019165)
Descriptors: MW 437.91, ALogP 2.12, HBA 5, HBD 2, PSA 116.67, QED 0.71
Compound (SMILES): N#Cc1ccccc1N1CCN(C[C@H](O)COC[C@H](Cc2ccccc2)NC(=O)c2ccncc2)CC1
InChIKey: JEJVZDGRLIYMOS-SVBPBHIXSA-N
Target: Cathepsin B (SINGLE PROTEIN), Homo sapiens
UniProt: P07858
Assay: Inhibition of human cathepsin B
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 499.62, ALogP 2.49, HBA 7, HBD 2, PSA 101.72, QED 0.42
Compound (SMILES): COc1cc2c(cc1C1=CCN(C)CCC1)N=C(N)C21CCC1
InChIKey: VMVRYCYPSDCNEH-UHFFFAOYSA-N
Target: Histone-lysine N-methyltransferase EHMT2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q96KQ7
Assay: Inhibition of G9a (unknown origin) using H3 as peptide substrate measured after 20 mins by fluorescence based analysis
Measurement: IC50 = 75.7 nM (pChEMBL 7.119999885559082)
Descriptors: MW 311.43, ALogP 3.23, HBA 4, HBD 1, PSA 50.85, QED 0.91
Compound (SMILES): C=CC(=O)N1CCCCCCCn2cc(c3ccccc32)-c2ccnc(n2)Nc2cc1c(OCCCF)cc2F
InChIKey: MASVXNVQOMUHQU-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR L858R/T790M double mutant (unknown origin)
Measurement: IC50 = 25.7 nM (pChEMBL 7.590000152587891)
Descriptors: MW 545.63, ALogP 7.2, HBA 6, HBD 1, PSA 72.28, QED 0.21
Compound (SMILES): COCC(NC(=O)C(C)C)C(=O)Nc1nnc(Cc2ccc([N+](=O)[O-])cc2)s1
InChIKey: IJTNSOILMGGGCG-UHFFFAOYSA-N
Target: Ubiquitin carboxyl-terminal hydrolase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O75604
Assay: Inhibition of human His-tagged USP2 (259 to 605 residues) using ubiquitin rhodamine 110 110 as substrate preincubated for 15 to 20 mins followed by enzyme addition and measured after 25 mins by fluorometric assay
Measurement: IC50 > 25000 nM (pChEMBL 4.6020002365112305)
Descriptors: MW 407.45, ALogP 1.76, HBA 8, HBD 2, PSA 136.35, QED 0.48
Compound (SMILES): CCCCOc1cc(NC(=O)c2nnn(-c3cc(OC)ccc3OC)c2C)cc(C(C)(C)C)c1
InChIKey: LPESWHGIWUIELX-UHFFFAOYSA-N
Target: Nuclear receptor subfamily 1 group I member 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O75469
Assay: Antagonist activity at human PXR in human HepG2 cells co-expressing luciferase gene under control of CYP3A4 promoter assessed as inhibition in rifampicin-induced receptor activation incubated for 24 hrs by luminescence based analysis
Measurement: IC50 = 210 nM (pChEMBL 6.679999828338623)
Descriptors: MW 466.58, ALogP 5.32, HBA 7, HBD 1, PSA 87.5, QED 0.43
Compound (SMILES): COc1cc(/C=C2/CN(C(C)=O)C(Cc3ccccc3)CN2C(=O)c2ccccc2)cc2c1OCO2
InChIKey: NOOJBZHDPURBGQ-QFEZKATASA-N
Target: Sterol O-acyltransferase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O75908
Assay: Inhibition of SOAT2 (unknown origin)
Measurement: IC50 = 6700 nM (pChEMBL 5.170000076293945)
Descriptors: MW 484.55, ALogP 4.38, HBA 5, HBD 0, PSA 68.31, QED 0.54
Compound (SMILES): CC(C)CN(c1ccc(O)c(C(=O)O)c1)S(=O)(=O)c1ccc(-c2ccccc2)cc1
InChIKey: XXRLVLIOGDKSJS-UHFFFAOYSA-N
Target: Bcl-2-like protein 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q07817
Assay: fluorescence polarization competition assay (FPCA): Molecular modeling and SILCS functional group affinity mapping (FragMaps) of the Mcl-1 binding site indicated that the carboxylic acid of designed molecule 3a (FIG. 1C) would occupy an energetically favorable region, associated with a salt bridge interaction with R263 of the Mcl-1 binding site, while the ring of the naphthyl core would bind in the p3 pocket demarcated by a favorable non-polar FragMap. The aniline was directed into the hydrophobic p2 pocket, which is also demarcated by a nonpolar FragMap. With the molecular modeling data in hand, compound 3a was then synthesized according to Scheme 1-2.Briefly, commercially available 1-hydroxy-2-naphthoic acid (4) was regioselectively 4-chlorosulfonylated to yield 5, which was isolated by pouring over ice and used without further purification. Sulfonyl chloride 5 was next reacted with 4-bromoaniline to furnish the target molecule 3a in excellent overall yield (83%). Evaluation of 3a in a fluorescence polarization competition assay (FPCA) indicated that it disrupted the Mcl-1-Bak-BH3 PPI with an IC50 of 10.9 μM, corresponding to a Ki of 2.76 μM. Given the ability of 3a to inhibit Mcl-1, a structure-activity relationship (SAR) study was developed, the results of which are presented in the tables below.
Measurement: Ki = 13851 nM (pChEMBL 4.860000133514404)
Descriptors: MW 425.51, ALogP 4.61, HBA 4, HBD 2, PSA 94.91, QED 0.58
Compound (SMILES): CCN(Cc1cc(C)n(C[C@@H]2C[C@H]2C#N)c(=O)c1)c1ccc(F)cc1
InChIKey: DGIGAYPQXQSHGW-IRXDYDNUSA-N
Target: Glutamate receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P42262
Assay: Displacement of [3H]-HBT1 from His-tagged GluA2-AMPA receptor LBD (unknown origin) in presence of glutamate by scintillation proximity assay
Measurement: IC50 = 10000 nM (pChEMBL 5)
Descriptors: MW 339.41, ALogP 3.48, HBA 4, HBD 0, PSA 49.03, QED 0.81
Compound (SMILES): NS(=O)(=O)c1ccc(N2CCN(/C(=N/O)c3ccc(F)cc3)CC2)cc1
InChIKey: ZLWIKBNNYLCANS-LVZFUZTISA-N
Target: Carbonic anhydrase 9 (SINGLE PROTEIN), Homo sapiens
UniProt: Q16790
Assay: Inhibition of human recombinant carbonic anhydrase 9 assessed as inhibition constant preincubated for 15 mins by phenol red dye based stopped flow CO2 hydration assay
Measurement: Ki = 1339 nM (pChEMBL 5.869999885559082)
Descriptors: MW 378.43, ALogP 1.43, HBA 5, HBD 2, PSA 99.23, QED 0.36
Compound (SMILES): CCc1sc(-c2csc(Nc3cc(Cl)cc(Cl)c3)n2)nc1-c1ccccc1
InChIKey: AFWXBGVTEYITGX-UHFFFAOYSA-N
Target: Cytochrome P450 1A2 (SINGLE PROTEIN), Homo sapiens
UniProt: P05177
Assay: Inhibition of recombinant human CYP1A2 using 7-ethyl-0-resorufin as substrate incubated for 30 mins in presence of NADPH by EROD assay
Measurement: IC50 = 226.9 nM (pChEMBL 6.639999866485596)
Descriptors: MW 432.4, ALogP 7.55, HBA 5, HBD 1, PSA 37.81, QED 0.35
Compound (SMILES): CC(=O)N1c2ncc(NC(=O)CCc3cccc(Cl)c3)cc2C2(CCCCC2)C1(C)C
InChIKey: PKSIZFDDWHDTHP-UHFFFAOYSA-N
Target: Follicle-stimulating hormone receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P23945
Assay: Antagonist activity at human FSHR expressed in HEK293 cells assessed as reduction in cAMP production incubated for 2 hrs by Eu-cAMP tracer based TR-FRET assay
Measurement: IC50 = 1440 nM (pChEMBL 5.840000152587891)
Descriptors: MW 439.99, ALogP 5.65, HBA 3, HBD 1, PSA 62.3, QED 0.67
Compound (SMILES): CC(=O)N1c2cnc(NC(=O)OCC3(C(F)(F)F)CC3)nc2C2(CCC(F)(F)CC2)C1(C)C
InChIKey: XEGSXAZIAWXAJO-UHFFFAOYSA-N
Target: Follicle-stimulating hormone receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P23945
Assay: Antagonist activity at human FSHR expressed in HEK293 cells assessed as reduction in cAMP production incubated for 2 hrs by Eu-cAMP tracer based TR-FRET assay
Measurement: IC50 = 156 nM (pChEMBL 6.809999942779541)
Descriptors: MW 476.45, ALogP 4.96, HBA 5, HBD 1, PSA 84.42, QED 0.62
Compound (SMILES): Cc1c(Cl)ccc2c(/C=C3\NC(=O)N(Cc4ccc(F)c(F)c4)C3=O)c[nH]c12
InChIKey: OEXMEVPQEPHTAQ-IDUWFGFVSA-N
Target: E3 ubiquitin-protein ligase Mdm2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q00987
Assay: Inhibition of MDM2 (unknown origin)
Measurement: IC50 = 30 nM (pChEMBL 7.519999980926514)
Descriptors: MW 401.8, ALogP 4.5, HBA 2, HBD 2, PSA 65.2, QED 0.5
Compound (SMILES): COc1ccc(-n2ncc3c(Nc4ccc(OC)c(Cl)c4)ncnc32)cc1
InChIKey: JUHSCKFRDYSOPZ-UHFFFAOYSA-N
Target: Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (SINGLE PROTEIN), Homo sapiens
UniProt: Q8TBX8
Assay: Inhibition of GST-fused human recombinant chimeric PI5P4Kgamma+ harboring PI5P4Kalpha-like mutations expressed in Escherichia coli BL21(DE3) incubated for 60 mins by ADP-Glo assay
Measurement: IC50 = 12589.25 nM (pChEMBL 4.900000095367432)
Descriptors: MW 381.82, ALogP 4.23, HBA 7, HBD 1, PSA 74.09, QED 0.56
Compound (SMILES): O=C1N[C@H]2C[C@@H](C2)OCc2cccc(n2)Nc2cc([nH]n2)[C@H]2CC[C@H](C2)O1
InChIKey: LAQCQSKKZIRXFW-MHEUCROKSA-N
Target: CDK6/cyclin D3 (PROTEIN COMPLEX), Homo sapiens
UniProt: P30281
Assay: Inhibition of CDK6/Cyclin D3 (unknown origin)
Measurement: IC50 = 34 nM (pChEMBL 7.46999979019165)
Descriptors: MW 369.43, ALogP 2.97, HBA 6, HBD 3, PSA 101.16, QED 0.66
Compound (SMILES): O=c1[nH]c(/C=C/c2cccc(F)c2)nc2ccccc12
InChIKey: ZFGIVIZXCYOWBK-CMDGGOBGSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR (unknown origin)
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 266.27, ALogP 3.23, HBA 2, HBD 1, PSA 45.75, QED 0.77
Compound (SMILES): Cn1cnc2c(c(-c3ccc(O)c(C#N)c3)cn2CC(=O)Nc2ccncc2Cl)c1=O
InChIKey: OMQBAUBAIKPPEO-UHFFFAOYSA-N
Target: B-cell lymphoma 6 protein (SINGLE PROTEIN), Homo sapiens
UniProt: P41182
Assay: Inhibition of BCL6 (unknown origin) stably expressed in human SU-DHL-4 cells incubated for 2 days by luminescence based microplate reader analysis
Measurement: IC50 = 2100 nM (pChEMBL 5.679999828338623)
Descriptors: MW 434.84, ALogP 2.67, HBA 8, HBD 2, PSA 125.83, QED 0.51
Compound (SMILES): N#Cc1ccccc1N1CCN(C[C@@H](O)COC[C@@H](Cc2ccccc2)NC(=O)C2CCN(C(=O)OCc3ccccc3)CC2)CC1
InChIKey: FCORXOBTLFNQOU-KKLWWLSJSA-N
Target: Cathepsin B (SINGLE PROTEIN), Homo sapiens
UniProt: P07858
Assay: Inhibition of human cathepsin B
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 639.8, ALogP 3.83, HBA 8, HBD 2, PSA 118.37, QED 0.29
Compound (SMILES): Cc1ccc(-c2noc(-c3cccc(OCC4CCN(Cc5ccc(F)cc5)CC4)c3)n2)cn1
InChIKey: OIQWPSGFYFVEPC-UHFFFAOYSA-N
Target: Acetylcholinesterase (SINGLE PROTEIN), Homo sapiens
UniProt: P22303
Assay: Inhibition of human AChE using ATC and BTC iodide as substrate preincubated for 5 mins followed by substrate addition and measured after 2 mins by DTNB reagent based assay
Measurement: IC50 = 2990 nM (pChEMBL 5.519999980926514)
Descriptors: MW 458.54, ALogP 5.54, HBA 6, HBD 0, PSA 64.28, QED 0.36
Compound (SMILES): CN1CCN(c2ccc(Nc3nc(Nc4ccc5[nH]ccc5c4)c4cn[nH]c4n3)cc2)CC1
InChIKey: OMTVOJFWRBBVMU-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of wild type EGFR (unknown origin) expressed in baculovirus expression system by ELISA
Measurement: IC50 = 127 nM (pChEMBL 6.900000095367432)
Descriptors: MW 439.53, ALogP 4.07, HBA 7, HBD 4, PSA 100.79, QED 0.33
Compound (SMILES): CC(=O)N1c2ccc(NC(=O)OCc3cccc(Cl)c3)cc2C2(CCCCC2)C1(C)C
InChIKey: MPKRDHKKGAKRPV-UHFFFAOYSA-N
Target: Follicle-stimulating hormone receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P23945
Assay: Antagonist activity at human FSHR expressed in HEK293 cells assessed as reduction in cAMP production incubated for 2 hrs by Eu-cAMP tracer based TR-FRET assay
Measurement: IC50 = 6000 nM (pChEMBL 5.21999979019165)
Descriptors: MW 440.97, ALogP 6.44, HBA 3, HBD 1, PSA 58.64, QED 0.6