lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): c1ccc(OCCNCC2CSC3(CCCCC3)O2)cc1
InChIKey: STPLWRDJTCMAMP-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 1A (SINGLE PROTEIN), Homo sapiens
UniProt: P08908
Assay: Displacement of [3H]8-OH-DPAT from recombinant human 5-HT1A receptor expressed in HeLa cell membranes after 30 mins by TopCount liquid scintillation counting method
Measurement: Ki = 22.91 nM (pChEMBL 7.639999866485596)
Descriptors: MW 307.46, ALogP 3.45, HBA 4, HBD 1, PSA 30.49, QED 0.82
Compound (SMILES): N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)Nc3cc(F)cc(F)c3F)CC2)C1
InChIKey: PYBFGQAKKRAPGX-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: In vitro JAK Kinase Assay: The catalytic domains of human JAK1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a. 781-1124) with an N-terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic activity of JAK1, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF). IC50s of compounds were measured for each kinase in the 40 microL reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. For the 1 mM IC50 measurements, ATP concentration in the reactions was 1 mM. Reactions were carried out at room temperature for 1 hr and then stopped with 20 μL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, Mass.). Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, Mass.)
Measurement: IC50 = 30 nM (pChEMBL 7.519999980926514)
Descriptors: MW 535.53, ALogP 3.86, HBA 7, HBD 2, PSA 118.76, QED 0.37
Compound (SMILES): O=C(O)[C@@H]1CCN1c1nc2ccccc2n([C@H]2C[C@H]3CCC[C@@H](C2)N3[C@H]2C[C@@H]3CCC[C@@H](C3)C2)c1=O
InChIKey: FQAQAGMTMTXLRQ-OGXPWPJRSA-N
Target: Delta-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41143
Assay: In Vitro Delta-Opioid Receptor Binding Assay: Radioligand dose-displacement assays used 0.2 nM [3H]-Naltrindole (NEN; 33.0 Ci/mmole) with 10-20 μg membrane protein (recombinant delta opioid receptor expressed in CHO-K1 cells; Perkin Elmer) in a final volume of 500 μL binding buffer (5 mM MgCl2, 5% DMSO, 50 mM Trizma base, pH 7.4). Non-specific binding was determined in the presence of 25 μM unlabeled naloxone. All reactions were performed in 96-deep well polypropylene plates for 1 h at a temperature of about 25 °C. Binding reactions were determined by rapid filtration onto 96-well Unifilter GF/C filter plates (Packard) presoaked in 0.5% polyethylenimine (Sigma-Aldrich). Harvesting was performed using a 96-well tissue harvester (Packard) followed by five filtration washes with 500 μL ice-cold binding buffer. Filter plates were subsequently dried at 50 °C. for 1-2 hours. Fifty μL/well scintillation cocktail (MicroScint20, Packard) was added and plates were counted in a Packard Top-Count for 1 min/well.
Measurement: Ki > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 490.65, ALogP 4.59, HBA 6, HBD 1, PSA 78.67, QED 0.68
Compound (SMILES): Cc1nc2c(C(=O)O)cc(N3CCOCC3)nn2c1Cc1cccc(C(F)(F)F)c1C
InChIKey: DKTMKUHYROTKCJ-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Binding affinity to human PI3Kgamma (144 to 1102 residues) expressed in mammalian expression system by KINOMEscan assay
Measurement: Kd = 5248 nM (pChEMBL 5.28000020980835)
Descriptors: MW 434.42, ALogP 3.49, HBA 6, HBD 1, PSA 79.96, QED 0.68
Compound (SMILES): CNCCN1CCC(OCc2cccc(-c3ccccc3)c2)CC1
InChIKey: OLFLGFYCUQONAR-UHFFFAOYSA-N
Target: Protein arginine N-methyltransferase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q99873
Assay: Inhibition of PRMT1 (unknown origin) assessed as inhibition of methylation activity measured after 3 hrs using [3H]-SAM by scintillation proximity assay
Measurement: IC50 > 5800 nM (pChEMBL 5.236999988555908)
Descriptors: MW 324.47, ALogP 3.55, HBA 3, HBD 1, PSA 24.5, QED 0.84
Compound (SMILES): O=C(c1ccc2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1)N1CC[C@@H](F)C1
InChIKey: FWLFRXVPNVBXGR-CQSZACIVSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Inhibition of hERG channel by electrophysiology
Measurement: IC50 = 25500 nM (pChEMBL 4.590000152587891)
Descriptors: MW 405.35, ALogP 4.62, HBA 4, HBD 0, PSA 55.32, QED 0.6
Compound (SMILES): CCCN1CC[C@H]2c3cc4ccccc4nc3[C@H](CC)[C@H]3CCC[C@@H]1[C@@H]32
InChIKey: GHQALVWJILAFPS-VCSLONGPSA-N
Target: Sigma non-opioid intracellular receptor 1 (SINGLE PROTEIN), Cavia porcellus
UniProt: Q60492
Assay: Displacement of [3H]pentazocine from guinea pig sigma1 receptor measured after 90 mins by microbeta scintillation counting method
Measurement: Ki = 70 nM (pChEMBL 7.159999847412109)
Descriptors: MW 348.53, ALogP 5.73, HBA 2, HBD 0, PSA 16.13, QED 0.7
Compound (SMILES): N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(S(=O)(=O)c3cccc(C#N)c3)CC2)C1
InChIKey: LHNVUHXNJWADTE-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: In Vitro JAK Kinase Assay: Compounds herein were tested for inhibitory activity of JAK targets according to the following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104. The catalytic domains of human JAK1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a. 781-1124) with an N-terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic activity of JAK1, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF). IC50s of compounds were measured for each kinase in the 40 microL reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. For the 1 mM IC50 measurements, ATP concentration in the reactions was 1 mM. Reactions were carried out at room temperature for 1 hr and then stopped with 20 μL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, Mass.). Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, Mass.).
Measurement: IC50 > 30 nM (pChEMBL 7.5229997634887695)
Descriptors: MW 527.61, ALogP 2.47, HBA 9, HBD 1, PSA 147.59, QED 0.4
Compound (SMILES): O=C(NO)c1ccc(Cn2cccn2)cc1
InChIKey: DUGDSZFLAKVUEC-UHFFFAOYSA-N
Target: Protein deacetylase HDAC6 (SINGLE PROTEIN), Mus musculus
UniProt: Q9Z2V5
Assay: Inhibition of HDAC6 in mouse N2A cells assessed as increase in alpha tubulin acetylation
Measurement: EC50 = 932 nM (pChEMBL 6.03000020980835)
Descriptors: MW 217.23, ALogP 1.05, HBA 4, HBD 2, PSA 67.15, QED 0.6
Compound (SMILES): Cc1cncc(-c2cc3c(cnn3-c3cccc(N4CCNCC4)n3)nn2)n1
InChIKey: SJECHZVGJJSCJC-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase pim-1 (SINGLE PROTEIN), Homo sapiens
UniProt: P11309
Assay: In Vitro Cell Proliferation Potency Assay: BaF3, a murine interleukin-3 dependent pro-B cell line, parental cells, BaF3 PIM1 cells, BaF3 PIM2 cells, and MM1.S (multiple myeloma) cells were seeded at 2 k/well, 5 k/well, 5 k/well, and 10 k/well respectively, in a 384-well plate, at 45 μL/well. Test compound was added at 5 μL/well. BaF3 cells (parental and transfected) were incubated overnight, while MM1.S cells were incubated for 72 hours at 37° C., 5% CO2. CELL TITER GLO® Reagent (Promega) was added at 50 μL/well, the plates were incubated for 30 minutes, and their luminescence read on an HT Analyst.
Measurement: IC50 = 236 nM (pChEMBL 6.630000114440918)
Descriptors: MW 373.42, ALogP 1.39, HBA 9, HBD 1, PSA 97.54, QED 0.58
Compound (SMILES): N#CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
InChIKey: NDXJCTYWGYPGPM-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase pim-1 (SINGLE PROTEIN), Homo sapiens
UniProt: P11309
Assay: In Vitro Cell Proliferation Potency Assay: BaF3, a murine interleukin-3 dependent pro-B cell line, parental cells, BaF3 PIM1 cells, BaF3 PIM2 cells, and MM1.S (multiple myeloma) cells were seeded at 2 k/well, 5 k/well, 5 k/well, and 10 k/well respectively, in a 384-well plate, at 45 μL/well. Test compound was added at 5 μL/well. BaF3 cells (parental and transfected) were incubated overnight, while MM1.S cells were incubated for 72 hours at 37° C., 5% CO2. CELL TITER GLO® Reagent (Promega) was added at 50 μL/well, the plates were incubated for 30 minutes, and their luminescence read on an HT Analyst.
Measurement: IC50 = 518 nM (pChEMBL 6.289999961853027)
Descriptors: MW 399.46, ALogP 2, HBA 9, HBD 1, PSA 100.48, QED 0.56
Compound (SMILES): CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(c5ncc(C(=O)NO)cn5)CC4)ccc3OCC)nc12
InChIKey: WNMRXNCXRGFIHO-UHFFFAOYSA-N
Target: Histone deacetylase 3/Nuclear receptor corepressor 2 (HDAC3/NCoR2) (PROTEIN COMPLEX), Homo sapiens
UniProt: Q9Y618
Assay: Inhibition of full length recombinant human C-terminal His-tagged HDAC3/N-terminal GST-tagged NCOR2 (395 to 489 residues) expressed in baculovirus infected Sf9 cells using fluorogenic HDAC substrate after 30 mins by fluorescence analysis
Measurement: IC50 = 36 nM (pChEMBL 7.440000057220459)
Descriptors: MW 597.66, ALogP 1.09, HBA 12, HBD 3, PSA 188.53, QED 0.19
Compound (SMILES): Cc1nn(-c2ccccc2)cc1CN1CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC1
InChIKey: QIMGORSOWHPBSK-UHFFFAOYSA-N
Target: Monoglyceride lipase (SINGLE PROTEIN), Homo sapiens
UniProt: Q99685
Assay: Inhibition of MGLL derived from human PC3 cell lysates preincubated for 30 mins followed by JW912 addition after 30 mins by gel-based ABPP assay
Measurement: IC50 = 230 nM (pChEMBL 6.639999866485596)
Descriptors: MW 450.38, ALogP 3.93, HBA 5, HBD 0, PSA 50.6, QED 0.66
Compound (SMILES): C1=C(CCN2CCc3ccccc3C2)CCc2ccccc21
InChIKey: UXAXXXXPTUTANS-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 1A (SINGLE PROTEIN), Homo sapiens
UniProt: P08908
Assay: Displacement of [3H]-8-OH-DPAT from human 5-HT1A receptor by liquid scintillation counting method
Measurement: Ki = 138 nM (pChEMBL 6.860000133514404)
Descriptors: MW 289.42, ALogP 4.46, HBA 1, HBD 0, PSA 3.24, QED 0.81
Compound (SMILES): Cc1c(Cc2ccccc2)nnc(N2CCN(c3cnc(C(O)CO)cn3)[C@H](C)C2)c1C
InChIKey: GRPLFVZGLYQPHG-XESZBRCGSA-N
Target: Protein smoothened (SINGLE PROTEIN), Homo sapiens
UniProt: Q99835
Assay: Displacement of radio-labeled smoothened agonist from human Smo by radio-ligand competition binding assay
Measurement: IC50 = 100 nM (pChEMBL 7)
Descriptors: MW 434.54, ALogP 2.22, HBA 8, HBD 2, PSA 98.5, QED 0.61
Compound (SMILES): COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CN(/C(=N/C#N)N2CCCC2)CCO1
InChIKey: PGISXUXCINKXKL-URGPHPNLSA-N
Target: Receptor tyrosine-protein kinase erbB-2 (SINGLE PROTEIN), Homo sapiens
UniProt: P04626
Assay: Inhibition of recombinant human N-terminal GST His6-tagged thrombin cleavage site-fused ErbB2 kinase domain (Q679 to V1255 residues) expressed in baculovirus infected insect Sf9 cells using biotinylated poly-EY as substrate after 60 mins by alphascreen assay
Measurement: IC50 < 50 nM (pChEMBL 7.301000118255615)
Descriptors: MW 556.45, ALogP 4.7, HBA 8, HBD 1, PSA 108.13, QED 0.26
Compound (SMILES): C[C@@H]1CN(c2sc(Br)nc2-c2nc3ccccc3[nH]2)CCN1C(=O)Cn1cnc2cccnc21
InChIKey: VSHOBSIPZJJYRP-CQSZACIVSA-N
Target: C-X-C chemokine receptor type 3 (SINGLE PROTEIN), Homo sapiens
UniProt: P49682
Assay: Antagonist activity at recombinant human CXCR3 in human U2SO cells assessed as reduction in CXCL10-induced beta-arrestin recruitment by TANGO assay
Measurement: IC50 = 126 nM (pChEMBL 6.900000095367432)
Descriptors: MW 537.45, ALogP 3.93, HBA 8, HBD 1, PSA 95.83, QED 0.37
Compound (SMILES): CC(C)NC(=O)N(CCN1[C@@H]2CC[C@H]1C[C@@H](c1cccc(C(N)=O)c1)C2)CC1CCCCC1
InChIKey: HQFCOIBMSKWMCF-QEIWAGNOSA-N
Target: Kappa-type opioid receptor (SINGLE PROTEIN), Cavia porcellus
UniProt: P41144
Assay: Displacement of [3H]-DPN from guinea pig kappa opioid receptor expressed in CHO-K1 cell membranes by radioligand binding assay
Measurement: Ki = 0.1585 nM (pChEMBL 9.800000190734863)
Descriptors: MW 454.66, ALogP 4.5, HBA 3, HBD 2, PSA 78.67, QED 0.61
Compound (SMILES): CC(C)n1cc(-c2cc(-c3ccc(CN4CCOCC4)cc3)cnc2N)nn1
InChIKey: CFVWLNQPGCBNKV-UHFFFAOYSA-N
Target: Leucine-rich repeat serine/threonine-protein kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q5S007
Assay: Inhibition LRRK2 G2019S mutant (unknown origin) Ser935 phosphorylation in HEK293 cells
Measurement: IC50 = 920 nM (pChEMBL 6.039999961853027)
Descriptors: MW 378.48, ALogP 3, HBA 7, HBD 1, PSA 82.09, QED 0.73
Compound (SMILES): COc1cc(OC)cc(N(CC2CC2)c2ccc3ncc(-c4cnn(CCF)c4)nc3c2)c1
InChIKey: SEVOZKSFLJRZMK-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Inhibition of VEGFR2 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in presence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 447.51, ALogP 5.03, HBA 7, HBD 0, PSA 65.3, QED 0.36
Compound (SMILES): CC(C)(C)C(=O)Nc1ncccc1CN1CCC(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)CC1
InChIKey: FLPFOUMYJHCJLQ-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: Inhibition of human N-terminal His-tagged JAK2 catalytic domain (828 to 1132 residues) expressed in baculovirus infected insect cells assessed as decrease in phosphorylation of biotinylated peptide substrate after 1 hr in presence of 1 mM ATP by HTRF method
Measurement: IC50 > 10 nM (pChEMBL 8)
Descriptors: MW 552.69, ALogP 3.79, HBA 9, HBD 2, PSA 131.65, QED 0.35
Compound (SMILES): O=C1NCCCc2c1c1ccccc1n2CCc1ccccc1
InChIKey: MGCVMPGXEBMMCL-UHFFFAOYSA-N
Target: Cholinesterase (SINGLE PROTEIN), Homo sapiens
UniProt: P06276
Assay: Inhibition of human BChE pretreated for 20 mins followed by butyrylthiocholine iodide substrate addition measured for 5 mins by Ellman's method
Measurement: IC50 = 13 nM (pChEMBL 7.889999866485596)
Descriptors: MW 304.39, ALogP 3.56, HBA 2, HBD 1, PSA 34.03, QED 0.79
Compound (SMILES): Cc1ccc(C(=O)N2CCOC[C@H]2Cc2cc(F)cc(-n3nccn3)c2)c(-n2nccn2)c1
InChIKey: JOKDLAIJHCOJRF-HXUWFJFHSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: CYP3A4 Inhibition Assay: The CYP3A4 inhibition assay was performed using human liver microsomes and testosterone 6'-hydroxylation as a P450 isoform-specific marker. In a total volume of 150 uL, 14C-testosterone at a final concentration of 40 uM in a 100 mM phosphate buffer (pH 7.4) was incubated in a 96-well plate with 0.3 mg/mL of human liver microsomes in an Eppendorf thermomixer at 37° C. and 400 rpm. A 1.0 uL-aliquot of the 150-fold concentrated compound stock solution, prepared in DMSO, was added to yield final inhibitor concentrations of 0, 0.1, 0.5, 1.0, 5.0, 10, 25, and 50 uM. The reaction was initiated by addition of 15 uL of the NADPH-regenerating system containing the glucose-6-phosphate dehydrogenase and terminated after 7 min with a 75 uL-aliquot of methanol. After centrifugation at 465 g and 4° C. for 20 min, a 50 uL-aliquot of the supernatant was submitted to HPLC according to the method described below.
Measurement: IC50 = 40000 nM (pChEMBL 4.400000095367432)
Descriptors: MW 447.47, ALogP 2.38, HBA 8, HBD 0, PSA 90.96, QED 0.47
Compound (SMILES): COc1ccc(-c2ccccc2N2CCN(CCCCCC(=O)N[C@H](C)c3ccc(C#N)cc3)CC2)cc1
InChIKey: LPOLFZKIDWJURQ-RUZDIDTESA-N
Target: D(2) dopamine receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P14416
Assay: Displacement of [3H]raclopride from human dopamine D2L receptor expressed in HEK293 cell membranes after 1 hr by microbeta counting analysis
Measurement: Ki = 243 nM (pChEMBL 6.610000133514404)
Descriptors: MW 510.68, ALogP 5.79, HBA 5, HBD 1, PSA 68.6, QED 0.33
Compound (SMILES): CC(C)[C@H](NS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(=O)O
InChIKey: CUKATAAPVFYVIL-QHCPKHFHSA-N
Target: 72 kDa type IV collagenase (SINGLE PROTEIN), Homo sapiens
UniProt: P08253
Assay: Inhibition of recombinant human AMPA-activated MMP2 using Cy3-PLGLK(Cy5Q)AR-NH2 as substrate measured after 40 mins by spectrofluorimetric method
Measurement: IC50 = 8.3 nM (pChEMBL 8.079999923706055)
Descriptors: MW 534.59, ALogP 2.91, HBA 6, HBD 4, PSA 158.32, QED 0.26
Compound (SMILES): O=C1C[C@]23CCN(CC4CC4)[C@H](Cc4ccc(O)cc42)[C@]3(O)C[C@@H]1CCO
InChIKey: KHDWRJGGHQWNJY-JJCGOBCMSA-N
Target: Kappa-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41145
Assay: [35S]GTPγS Functional Assay: Functional [35S]GTPγS binding assays were conducted as follows. κ opioid receptor membrane solution was prepared by sequentially adding final concentrations of 0.026 μg/μl κ membrane protein (in-house), 10 μg/mL saponin, 3 μM GDP and 0.20 nM [35S]GTPγS to binding buffer (100 mM NaCl, 10 mM MgCl2, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190 μl/well) was transferred to 96-shallow well polypropylene plates containing 10 μl of 20× concentrated stock solutions of agonist prepared in DMSO. Plates were incubated for 30 min at a temperature of about 25° C. with shaking. Reactions were terminated by rapid filtration onto 96-well Unifilter GF/B filter plates (Perkin Elmer, Shelton, Conn.) using a 96-well tissue harvester (Packard) and followed by three filtration washes with 200 μl ice-cold binding buffer (10 mM NaH2PO4, 10 mM Na2HPO4, pH 7.4). Filter plates were subsequently dried at 50° C. for 2-3 hours. Fifty μl/well scintillation cocktail (Perkin Elmer, Shelton, Conn.) was added and plates were counted in a Packard Top-Count for 1 min/well.
Measurement: EC50 = 4.82 nM (pChEMBL 8.319999694824219)
Descriptors: MW 371.48, ALogP 1.76, HBA 5, HBD 3, PSA 81, QED 0.75
Compound (SMILES): Cc1cccc2cc(C(C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
InChIKey: UMBOVTDDENNROQ-UHFFFAOYSA-N
Target: PI3K p110 beta/p85 alpha (PROTEIN COMPLEX), Homo sapiens
UniProt: P27986
Assay: Inhibition of N-terminal His6-tagged recombinant full-length human p110beta/untagged recombinant full length p85alpha expressed in baculovirus infected Sf21 cells using phosphatidylinositol as substrate in presence of gamma-32P-ATP after 5 mins by thin layer chromatographic method
Measurement: IC50 < 10000 nM (pChEMBL 5)
Descriptors: MW 396.45, ALogP 4.14, HBA 6, HBD 2, PSA 88.49, QED 0.48
Compound (SMILES): C[C@H](c1cc(F)cc(F)c1)N(C(=O)c1ccccc1)[C@@H](C(N)=O)c1ccccc1
InChIKey: NNXPFEMWLZLAHM-QVKFZJNVSA-N
Target: Transient receptor potential cation channel subfamily A member 1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75762
Assay: Antagonist activity at human recombinant TRPA1 expressed in HEK293 cells assessed as inhibition of AITC-induced calcium increase by Fluo-4 AM based assay
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 394.42, ALogP 4.39, HBA 2, HBD 1, PSA 63.4, QED 0.67
Compound (SMILES): O=C(O)c1c(N2CCCCC2)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
InChIKey: CXDOFNPXCPTGNV-UHFFFAOYSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin)
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 401.29, ALogP 5.9, HBA 3, HBD 1, PSA 53.43, QED 0.59
Compound (SMILES): N#Cc1ccc(NC(=O)N2CCCc3ccc(C=O)nc32)nc1
InChIKey: DNJLKERWZGKXBF-UHFFFAOYSA-N
Target: Fibroblast growth factor receptor 4 (SINGLE PROTEIN), Mus musculus
UniProt: Q03142
Assay: Inhibition of FGFR4 in mouse BAF3 cells assessed as reduction in cell viability incubated for 2 days by cell proliferation assay
Measurement: IC50 = 171 nM (pChEMBL 6.769999980926514)
Descriptors: MW 307.31, ALogP 2.15, HBA 5, HBD 1, PSA 98.98, QED 0.86
Compound (SMILES): COc1cc(N2CCC(N3CCN(CCS(C)(=O)=O)CC3)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
InChIKey: BUTRIAZZMQWNMT-UHFFFAOYSA-N
Target: Receptor tyrosine-protein kinase erbB-2 (SINGLE PROTEIN), Homo sapiens
UniProt: P04626
Assay: Inhibition of recombinant human full length ErbB2 expressed in baculovirus expression system assessed as decrease in transfer of gamma-phosphate from ATP onto tyrosine residue of biotinylated peptide substrate preincubated for 1 hr followed by substrate addition measured after 90 mins by HTRF method
Measurement: IC50 < 1000 nM (pChEMBL 6)
Descriptors: MW 851.98, ALogP 6.38, HBA 13, HBD 2, PSA 146.53, QED 0.13
Compound (SMILES): N#CCC1(n2cc(C(N)=O)c(Nc3ccc([S+]([O-])C(F)F)cc3)n2)CCC(NC2CCCCC2)CC1
InChIKey: DWSPHXUGBRSRHB-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: HTRF Biochemical Assay: The reactions employed a common peptide substrate, LCB-EQEDEPEGDYFEWLW-NH2 (in-house). The basic assay protocol is as follows: First, 250 nL of diluted compounds in DMSO were dispensed into the wells of a dry 384-well Black plate (Greiner #781076) using a Labcyte Echo 555 acoustic dispenser. Subsequent reagent additions employed an Agilent Bravo. Next, 18 uL of 1.11x enzyme and 1.11x substrate in 1x assay buffer (Invitrogen kinase buffer # PV3189, 2 mM DTT, 0.05% BSA) were added to the wells and shaken and then preincubated for 30 minutes at room temperature to allow compound binding to equilibrate. After equilibration, 2 uL of 10xATP in 1x assay buffer was added to initiate the kinase reaction and the plates were shaken and then incubated at room temperature for 120 minutes. At the end of the incubation, 20 uL of 2x stop buffer (streptavidin-Dylight 650 (Thermo #84547B/100 mL), Eu-tagged pY20 antibody (Perkin Elmer #AD0067), EDTA, HEPES, and Triton) was added to quench the reaction.
Measurement: IC50 > 1496 nM (pChEMBL 5.824999809265137)
Descriptors: MW 518.63, ALogP 4.53, HBA 7, HBD 3, PSA 131.82, QED 0.42
Compound (SMILES): Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cc(C(C)C)nc(N2CCOCC2)n1
InChIKey: IHBLFXPNFUIIDO-UHFFFAOYSA-N
Target: RAF proto-oncogene serine/threonine-protein kinase (SINGLE PROTEIN), Homo sapiens
UniProt: P04049
Assay: In Vitro Enzyme Assay: Final assay conditions were 4 pM cRaf, 3 uM ATP, 10 nM biotin tagged MEK1 kinase dead protein substrate. Reactions were performed in Greiner384 well plates, catalog #784075. Reaction buffer was 50 mM Tris, pH 7.5, 50 mM NaCl, 10 mM MgCl2, 0.01% Tween-20, 0.05% BSA and 1 mM DTT. 5 ul of 2×cRaf plus MEK1 were dispensed into plates containing 0.25 ul of compound in 100% DMSO and incubated at room temperature for 30 minutes. Reactions were started by addition of 5 ul of 2×ATP. Reactions were run for two hours and terminated by addition of 10 ul of 2× antibody and Alphascreen bead mixture in Stop Buffer. Stop Buffer was 50 mM Tris, pH 7.5, 0.005% Tween-20, 25 mM EDTA.
Measurement: IC50 = 1.018 nM (pChEMBL 8.989999771118164)
Descriptors: MW 484.52, ALogP 5.68, HBA 5, HBD 1, PSA 67.35, QED 0.5
Compound (SMILES): COc1cc(OC)cc(N(CCCN2CCC(N3CCCCC3)C2)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1
InChIKey: YOPGGAOPPHWDEP-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Inhibition of VEGFR2 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in presence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 = 7413.1 nM (pChEMBL 5.130000114440918)
Descriptors: MW 555.73, ALogP 5.14, HBA 9, HBD 0, PSA 71.78, QED 0.27
Compound (SMILES): C[C@H](Nc1ncnc(N)c1C#Cc1ccc(C(F)(F)F)cn1)c1nc2cccc(Cl)c2c(=O)n1-c1cc(F)cc(F)c1
InChIKey: AZSPQWBIRMTTHA-AWEZNQCLSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay: PI3K isoforms were assayed under initial rate conditions in the presence of 25 mM Hepes (pH 7.4), and 2xKm ATP (100-300 uM), 10 uM PIP2, 5% glycerol, 5 mM MgCl2, 50 mM NaCl, 0.05% (v/v) Chaps, 1 mM dithiothreitol, 1% (v/v) DMSO at the following concentrations for each isoform: PI3K alpha, beta, delta, and gamma at 50 picomolar (pM) and PI3Kgamma at 2 nanomolar (nM). After an assay reaction time of 30 minutes at 25° C., reactions were terminated with a final concentration of 10 mM EDTA, 10 nM labeled-PIP3, and 35 nM Europium labeled GRP-1 detector protein before reading TR-FRET on an Envision plate reader (Ex: 340 nm; Em: 615/665 nm; 100 us delay and 500 us read window).
Measurement: IC50 = 550 nM (pChEMBL 6.260000228881836)
Descriptors: MW 597.94, ALogP 5.68, HBA 8, HBD 2, PSA 111.61, QED 0.2
Compound (SMILES): N#C/C=C/[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
InChIKey: IFSRXMXZMSULFT-LEANHWHLSA-N
Target: Non-receptor tyrosine-protein kinase TYK2 (SINGLE PROTEIN), Homo sapiens
UniProt: P29597
Assay: Enzyme Assay: JAK1, JAK2, JAK3 and Tyk2 were purchased from Carna Biosciences, Inc. As the substrate, LANCE Ultra ULight-JAK1 Peptide (manufactured by PerkinElmer Co., Ltd. (PE)) was used. Dilute solutions of compounds and enzymes in assay buffer (50 mM HEPES pH7.5, 1 mM EGTA, 1 mM MgCl2, 2 mM DTT, 0.01% Tween20) were dispensed into wells of a 384-well black plate. After 5 minutes of preincubation, dilute solutions of the substrate and ATP (adenosine triphosphate) were added at a final concentration of 100 μM, and the plate was incubated at room temperature for 2 hours. After addition of a termination reagent containing EDTA (ethylenediamine tetraacetic acid) at a final concentration of 10 mM, LANCE Eu-W1024 Anti-phosphotyrosine (PT66) (manufactured by PE) was added, and after 1 hour of incubation, the fluorescences were measured with ARVO-HTS.
Measurement: IC50 = 140 nM (pChEMBL 6.849999904632568)
Descriptors: MW 292.35, ALogP 2.96, HBA 5, HBD 1, PSA 82.66, QED 0.74
Compound (SMILES): Cl.Clc1ccc2sc(CCCCN3CCc4c(Cl)cccc4C3)nc2c1
InChIKey: SWOUGAVDTXEVBX-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 1A (SINGLE PROTEIN), Homo sapiens
UniProt: P08908
Assay: Displacement of [3H]-8-OH-DPAT from human 5-HT1A receptor by liquid scintillation counting method
Measurement: Ki = 42 nM (pChEMBL 7.380000114440918)
Descriptors: MW 391.37, ALogP 5.98, HBA 3, HBD 0, PSA 16.13, QED 0.5
Compound (SMILES): O=C(CC(F)(F)F)N1CCCC(c2nnn3cnc4[nH]ccc4c23)C1
InChIKey: SHUVTQRKSSOWEE-UHFFFAOYSA-N
Target: Non-receptor tyrosine-protein kinase TYK2 (SINGLE PROTEIN), Homo sapiens
UniProt: P29597
Assay: Enzyme Assay: JAK1, JAK2, JAK3 and Tyk2 were purchased from Carna Biosciences, Inc. As the substrate, LANCE Ultra ULight-JAK1 Peptide (manufactured by PerkinElmer Co., Ltd. (PE)) was used. Dilute solutions of compounds and enzymes in assay buffer (50 mM HEPES pH7.5, 1 mM EGTA, 1 mM MgCl2, 2 mM DTT, 0.01% Tween20) were dispensed into wells of a 384-well black plate. After 5 minutes of preincubation, dilute solutions of the substrate and ATP (adenosine triphosphate) were added at a final concentration of 100 μM, and the plate was incubated at room temperature for 2 hours. After addition of a termination reagent containing EDTA (ethylenediamine tetraacetic acid) at a final concentration of 10 mM, LANCE Eu-W1024 Anti-phosphotyrosine (PT66) (manufactured by PE) was added, and after 1 hour of incubation, the fluorescences were measured with ARVO-HTS.
Measurement: IC50 = 570 nM (pChEMBL 6.239999771118164)
Descriptors: MW 352.32, ALogP 2.26, HBA 5, HBD 1, PSA 79.18, QED 0.77
Compound (SMILES): CCOc1cc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2cc1NC(=O)/C=C/CN1[C@H](C)CNC[C@@H]1C
InChIKey: WJGBEIOIHHBCIV-RRSRKQOQSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Irreversible inhibition of human recombinant GST-tagged JAK3 expressed in baculovirus infected Sf9 insect cells assessed as reduction in polyglutamic acid-tyrosine phosphorylation after 30 mins by ELISA
Measurement: IC50 = 8880 nM (pChEMBL 5.050000190734863)
Descriptors: MW 590.73, ALogP 5.35, HBA 9, HBD 3, PSA 109.23, QED 0.19
Compound (SMILES): Cc1n[nH]c2c1C(c1ccc(F)c(F)c1)c1c([nH]c(=O)[nH]c1=O)O2
InChIKey: QIMOSJIYZCZLKA-UHFFFAOYSA-N
Target: Indoleamine 2,3-dioxygenase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P14902
Assay: Inhibition of N-terminus 6xHis-tagged human IDO1 expressed in Escherichia coli M15 using L-tryptophan as substrate preincubated for 1 hr measured after 15 mins in presence of bovine liver and methylene blue by spectrophotometric analysis
Measurement: Ki = 297 nM (pChEMBL 6.53000020980835)
Descriptors: MW 332.27, ALogP 1.66, HBA 4, HBD 3, PSA 103.63, QED 0.49
Compound (SMILES): Cc1c(C)n(Cc2ccc(C(=O)NO)cc2)c2ccccc12
InChIKey: GQPCGGQDQRAYCE-UHFFFAOYSA-N
Target: Polyamine deacetylase HDAC10 (SINGLE PROTEIN), Homo sapiens
UniProt: Q969S8
Assay: Inhibition of dye-labeled tracer binding to HDAC10 (unknown origin) transfected in human HeLa cells measured after 2 hrs by nano-luciferase reporter gene-based BRET assay
Measurement: IC50 = 630.96 nM (pChEMBL 6.199999809265137)
Descriptors: MW 294.35, ALogP 3.43, HBA 3, HBD 2, PSA 54.26, QED 0.57
Compound (SMILES): O=C(COc1ccc2cc(C(O)(C(F)(F)F)C(F)(F)F)c(O)cc2c1)Nc1ccccc1
InChIKey: PGYDWDUBOQNKAR-UHFFFAOYSA-N
Target: Tyrosine-protein phosphatase non-receptor type 22 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9Y2R2
Assay: Inhibition of recombinant LYP (unknown origin) using pNPP as substrate by spectrophotometric method
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 459.34, ALogP 4.88, HBA 4, HBD 3, PSA 78.79, QED 0.48
Compound (SMILES): Cc1c(Cc2ccccc2)nnc(N2CCN(c3cnc(C(C)(C)O)cn3)CC2)c1C
InChIKey: KUGYAAOIRJCBOT-UHFFFAOYSA-N
Target: Protein smoothened (SINGLE PROTEIN), Homo sapiens
UniProt: Q99835
Assay: Displacement of radio-labeled smoothened agonist from human Smo by radio-ligand competition binding assay
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 418.55, ALogP 3.03, HBA 7, HBD 1, PSA 78.27, QED 0.68
Compound (SMILES): COC(=O)CCCCCN/C=C1\C(=O)C(O)=C(C(C)C)c2cc(C)c(-c3c(C)cc4c(c3O)/C(=C/NCCCCCC(=O)OC)C(=O)C(O)=C4C(C)C)c(O)c21
InChIKey: UUUJPIHQZOPRHX-DHQAUHHZSA-N
Target: Induced myeloid leukemia cell differentiation protein Mcl-1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q07820
Assay: Inhibition of FAM-Bid binding to human MCL1 expressed in Escherichia coli BL21 after 30 mins by fluorescence polarization assay
Measurement: Ki = 195 nM (pChEMBL 6.710000038146973)
Descriptors: MW 772.94, ALogP 7.73, HBA 12, HBD 6, PSA 191.72, QED 0.05
Compound (SMILES): O=C(c1ccc2cc(Oc3ccc(C(F)(F)F)cn3)ccc2n1)N1CCN(CC(F)(F)F)CC1
InChIKey: KJVYQCIXUQIREB-UHFFFAOYSA-N
Target: Sodium channel protein type 5 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q14524
Assay: Inhibition of human Nav 1.5 expressed in HEK293 cells at -90 mV holding potential by Whole cell voltage clamp electrophysiology assay
Measurement: IC50 = 33000 nM (pChEMBL 4.480000019073486)
Descriptors: MW 484.4, ALogP 4.76, HBA 5, HBD 0, PSA 58.56, QED 0.5
Compound (SMILES): CC(C)[C@H](C(=O)O)N(CCNC(=O)c1ccccc1)S(=O)(=O)c1ccc(-c2ccccc2)cc1
InChIKey: BKYHPXRQAHYJBN-XMMPIXPASA-N
Target: Matrix metalloproteinase-14 (SINGLE PROTEIN), Homo sapiens
UniProt: P50281
Assay: Inhibition of recombinant human MMP-14 catalytic domain pretreated for 4 hrs followed by Mca-Lys-Pro-Leu-Gly-Leu-Dap(Dnp)-Ala-Arg-NH2 fluorogenic substrate addition measured every 15 secs for 20 mins by fluorimetric assay
Measurement: IC50 = 1830 nM (pChEMBL 5.739999771118164)
Descriptors: MW 480.59, ALogP 3.88, HBA 4, HBD 2, PSA 103.78, QED 0.46
Compound (SMILES): COc1cc2c(Nc3ccc(Br)c(Cl)c3)ncnc2cc1OC1CCN(C)C1
InChIKey: UJTDMNARLIOVGT-UHFFFAOYSA-N
Target: Receptor tyrosine-protein kinase erbB-2 (SINGLE PROTEIN), Homo sapiens
UniProt: P04626
Assay: Inhibition of recombinant human N-terminal GST His6-tagged thrombin cleavage site-fused ErbB2 kinase domain (Q679 to V1255 residues) expressed in baculovirus infected insect Sf9 cells using biotinylated poly-EY as substrate after 60 mins by alphascreen assay
Measurement: IC50 = 1000 nM (pChEMBL 6)
Descriptors: MW 463.76, ALogP 4.88, HBA 6, HBD 1, PSA 59.51, QED 0.58
Compound (SMILES): COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(Nc4ccc5[nH]ncc5c4)n3)c3ccccc23)cn1
InChIKey: YGZKTIVAVURWEZ-UHFFFAOYSA-N
Target: Glycogen synthase kinase-3 alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P49840
Assay: GSK 3α Enzyme Inhibition Assay: The inhibitory activities of compounds of the invention against the GSK 3α enzyme isoform (Invitrogen), are evaluated by determining the level of activation/phosphorylation of the target peptide. The GSK3-α protein (500 ng/mL, 2.5 uL) is mixed with the test compound (2.5 uL at either 4 ug/mL, 0.4 ug/mL, 0.04 ug/mL, or 0.004 ug/mL) for 2 hr at RT. The FRET peptide (8 uM, 2.5 uL), which is a phosphorylation target for GSK3α, and ATP (40 uM, 2.5 uL) are then added to the enzyme/compound mixture and the resulting mixture incubated for 1 hr. Development reagent (protease, 5 uL) is added for 1 hr prior to detection in a fluorescence microplate reader (Varioskan Flash, ThermoFisher Scientific).
Measurement: IC50 > 1560 nM (pChEMBL 5.807000160217285)
Descriptors: MW 640.71, ALogP 7.57, HBA 10, HBD 4, PSA 156.79, QED 0.13
Compound (SMILES): CN1CCN(c2ccc(NC(=O)Nc3ccc(-c4cnco4)cc3)cc2)CC1
InChIKey: JPBBSEUTVZQXIV-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: Biochemical JAK and Tyk2 Kinase Assays: A panel of four LanthaScreen JAK biochemical assays (JAK1, 2, 3 and Tyk2) were carried in a common kinase reaction buffer (50 mM HEPES, pH 7.5, 0.01% Brij-35, 10 mM MgCl2, and 1 mM EGTA). Recombinant GST-tagged JAK enzymes and a GFP-tagged STAT1 peptide substrate were obtained from Life Technologies. Serially or discretely diluted compounds were pre-incubated with each of the four JAK enzymes and the substrate in white 384-well microplates (Corning) at ambient temperature for 1 h. ATP was subsequently added to initiate the kinase reactions in 10 μL total volume, with 1% DMSO. The final enzyme concentrations for JAK1, 2, 3 and Tyk2 are 4.2 nM, 0.1 nM, 1 nM, and 0.25 nM respectively; the corresponding Km ATP concentrations used are 25 μM, 3 μM, 1.6 μM, and 10 μM; while the substrate concentration is 200 nM for all four assays. Kinase reactions were allowed to proceed for 1 hour at ambient temperature before a 10 μL preparation of EDTA (10 mM final concentration) and Tb-anti-pSTAT1 (pTyr701) antibody (Life Technologies, 2 nM final concentration) in TR-FRET dilution buffer (Life Technologies) was added. The plates were allowed to incubate at ambient temperature for 1 h before being read on the EnVision reader (Perkin Elmer). Emission ratio signals (520 nm/495 nm) were recorded and utilized to calculate the percent inhibition values based on DMSO and background controls.For dose-response analysis, percent inhibition data were plotted vs. compound concentrations, and IC50 values were determined from a 4-parameter robust fit model with the Prism software (GraphPad Software). Results were expressed as pIC50 (negative logarithm of IC50) and subsequently converted to pKi (negative logarithm of dissociation constant, Ki) using the Cheng-Prusoff equation.
Measurement: Ki > 100 nM (pChEMBL 7)
Descriptors: MW 377.45, ALogP 3.74, HBA 5, HBD 2, PSA 73.64, QED 0.72
Compound (SMILES): N#CCC1(n2ccc(-c3ncnc4[nH]ccc34)c2)CN(C2CCN(C(=O)c3nc(C(F)(F)F)cs3)CC2)C1
InChIKey: LLALUBWLLLOTGO-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: In vitro JAK Kinase Assay: The catalytic domains of human JAK1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a. 781-1124) with an N-terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic activity of JAK1, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF). IC50s of compounds were measured for each kinase in the 40 microL reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. For the 1 mM IC50 measurements, ATP concentration in the reactions was 1 mM. Reactions were carried out at room temperature for 1 hr and then stopped with 20 μL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, Mass.). Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, Mass.)
Measurement: IC50 = 30 nM (pChEMBL 7.519999980926514)
Descriptors: MW 540.58, ALogP 4.13, HBA 8, HBD 1, PSA 106.73, QED 0.41
Compound (SMILES): CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)[C@H]1CC[C@H](N(C)C)CC1
InChIKey: CSABGPDBRQTQLK-MEMLXQNLSA-N
Target: Histone-lysine N-methyltransferase EZH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q15910
Assay: Inhibition Assay: Test compounds were serially diluted 3-fold in DMSO in a 10 point-curve and 1 uL was spotted into a 384-well microplate in duplicate using a Platemate Plus equipped with 384-channel head (Thermo Scientific). The final top concentration of test compounds in the assay was 10 uM. Positive control (100% inhibition standard) was 1 mM final concentration of SAH and negative control (0% inhibition standard) contained 1 uL of DMSO. Test compounds were then incubated for 30 minutes with 40 uL per well of wild-type EZH2 (final concentration was 4 nM), Y641F EZH2 (final concentration was 0.1 nM) and A677G and A687V EZH2 (for each, final concentration was 2nM) and peptide in 1x assay buffer (20 mM BICINE pH =7.6, 1 mM DTT, 0.002% TWEEN 20 (generic: polysorbate 20), 0.005% BSG). For the wild-type EZH2 and A677G EZH2 assays, biotinylated peptide H3:21-44 with unmethylated K27 was present at a final concentration of 200 nM, while in the A687V EZH2 assay, biotinylated peptide H3.
Measurement: IC50 = 8.2 nM (pChEMBL 8.09000015258789)
Descriptors: MW 506.61, ALogP 4.95, HBA 4, HBD 2, PSA 68.44, QED 0.56
Compound (SMILES): COc1cc(N2CCC(N3CCCCC3)CC2)c(Cl)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
InChIKey: RQSRBQKLFHZWQU-UHFFFAOYSA-N
Target: Receptor tyrosine-protein kinase erbB-2 (SINGLE PROTEIN), Homo sapiens
UniProt: P04626
Assay: Inhibition of recombinant human full length ErbB2 expressed in baculovirus expression system assessed as decrease in transfer of gamma-phosphate from ATP onto tyrosine residue of biotinylated peptide substrate preincubated for 1 hr followed by substrate addition measured after 90 mins by HTRF method
Measurement: IC50 < 1000 nM (pChEMBL 6)
Descriptors: MW 779.29, ALogP 8.86, HBA 10, HBD 2, PSA 109.15, QED 0.14
Compound (SMILES): CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
InChIKey: WXWCSPFQIXPFLD-YMXDCFFPSA-N
Target: Prostaglandin E2 receptor EP3 subtype (SINGLE PROTEIN), Homo sapiens
UniProt: P43115
Assay: Agonist activity at human recombinant EP3A receptor expressed in HEK293 cells assessed as effect on calcium accumulation by Fluo-4 AM dye based FLIPR assay
Measurement: EC50 = 12 nM (pChEMBL 7.920000076293945)
Descriptors: MW 429.58, ALogP 5.58, HBA 4, HBD 2, PSA 77.84, QED 0.46
Compound (SMILES): CCOc1ccc(F)c(F)c1[C@@H]1C[C@H](Cl)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
InChIKey: XMJOXAWFAYHGOA-ZFWWWQNUSA-N
Target: Orexin receptor type 2 (SINGLE PROTEIN), Homo sapiens
UniProt: O43614
Assay: In Vitro Assay: Intracellular Calcium Measurements : In Vitro Assay: Intracellular Calcium Measurements:Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F-12 with L-Glutamine) containing 300 g/ml G418, 100 U/ml penicillin, 100 g/ml streptomycin and 10% heat inactivated fetal calf serum (FCS). The cells are seeded at 20,000 cells/well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37° C. in 5% CO2. Human orexin-A as an agonist is prepared as 1 mM stock solution in MeOH:water (1:1), diluted in HBSS containing 0.1% bovine serum albumin (BSA), NaHCO3: 0.375 g/l and 20 mM HEPES for use in the assay at a final concentration of 3 nM.Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.1% bovine serum albumin (BSA), NaHCO3: 0.375 g/l and 20 mM HEPES. On the day of the assay, 50 μl of staining buffer (HBSS containing 1% FCS, 20 mM HEPES, NaHCO3: 0.375 g/l, 5 mM probenecid (Sigma) and 3 M of the fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO, containing 10% pluronic) is added to each well. The 384-well cell-plates are incubated for 50 min at 37° C. in 5% CO2 followed by equilibration at RT for 30 min before measurement.
Measurement: IC50 = 462 nM (pChEMBL 6.329999923706055)
Descriptors: MW 449.8, ALogP 5.34, HBA 3, HBD 0, PSA 38.77, QED 0.44
Compound (SMILES): CCCN1CCC(c2ccc(Nc3nccc(-c4c(-c5ccc(OCC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
InChIKey: WSNNKSMPKZCYGG-UHFFFAOYSA-N
Target: Receptor tyrosine-protein kinase erbB-2 (SINGLE PROTEIN), Homo sapiens
UniProt: P04626
Assay: Inhibition of recombinant human full length ErbB2 expressed in baculovirus expression system assessed as decrease in transfer of gamma-phosphate from ATP onto tyrosine residue of biotinylated peptide substrate preincubated for 1 hr followed by substrate addition measured after 90 mins by HTRF method
Measurement: IC50 < 1000 nM (pChEMBL 6)
Descriptors: MW 731.85, ALogP 9.12, HBA 9, HBD 2, PSA 105.91, QED 0.12
Compound (SMILES): C=Cc1cc(OC)cc(N(CC2CC2)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1.Cl
InChIKey: KMJPPWDZUJDQRH-UHFFFAOYSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 411.51, ALogP 5.23, HBA 6, HBD 0, PSA 56.07, QED 0.42
Compound (SMILES): Cc1ccc2c(Nc3ccc(Cl)cc3)nccc2c1NC(=O)c1csc2c(N)ncnc12
InChIKey: FHPTWZJZWOYCKG-UHFFFAOYSA-N
Target: Epithelial discoidin domain-containing receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q08345
Assay: Kinase Activity: The compounds prepared in Examples were tested for inhibitory activity against FMS, DDR1 and DDR2 kinases using Kinase Screening and Profiling Service (Invitrogen, U.S.).
Measurement: IC50 = 2 nM (pChEMBL 8.699999809265137)
Descriptors: MW 460.95, ALogP 5.78, HBA 7, HBD 3, PSA 105.82, QED 0.31
Compound (SMILES): CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(N4CCN(C(C)C)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
InChIKey: BLMVXEUFSWMMGH-UHFFFAOYSA-N
Target: Insulin-like growth factor 1 receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P08069
Assay: Inhibition of IGF1-induced human IGF1R autophosphorylation expressed in mouse NIH-3T3 cells preincubated for 2 hrs followed by IGF-1 induction measured after 15 mins by DELFIA
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 718.81, ALogP 7.67, HBA 10, HBD 2, PSA 109.15, QED 0.14
Compound (SMILES): COc1cc(C)c2c(C(=O)OCC34CCN(CC3)CC4)c[nH]c2c1
InChIKey: GLQNDTBVQMMHBA-UHFFFAOYSA-N
Target: Cytochrome P450 2D6 (SINGLE PROTEIN), Homo sapiens
UniProt: P10635
Assay: Cytochrome P450 Inhibition: Protocol 1: Studies were carried out in human liver microsomes. Human liver microsomes were purchased from BD Gentest. DMSO stocks were prepared for the test compounds. Aliquots of the DMSO solutions were diluted 1:3 by acetonitrile:ACN mixture (v/v: 40:60) to "400×" intermediate solutions, then further diluted by liver microsomes/buffer to "2×" intermediate solutions. "2×" intermediate solutions were mixed with "2×" NADPH/substrate solutions, which had been pre-warmed to 37° C. (final test compound concentrations were 10 μM, 3.3 μM, 1.1 μM, 0.37 μM, 0.122 μM, 0.041 μM, 0.0136 μM, and 0 μM). The plates were kept in a 37° C. water bath for the duration of the experiment. At the end of incubation (5 minutes for 3A4; 45 minutes for 2C19; 10 minutes for 1A2, 2C9, 2D6), 120 μL of acetonitrile was added into corresponding wells. After the final time point was sampled, the plates were shaken at a vibrator (IKA, MTS 2/4) for 10 mM (600 rpm/min) and then centrifuged at 5594 g for 15 mM (Thermo Multifuge×3R). Aliquots of the supernatant were removed, diluted 1:1 into distilled water, and analyzed by LC-MS/MS. The peak area response ratio to internal standard (PARR) of the compounds at 10 μM, 3.3 μM, 1.1 μM, 0.37 μM, 0.122 μM, 0.041 μM, and 0.0136 μM was compared to the PARR at 0 μM to determine the percent of metabolite generation from substrate at each test compound concentration.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 328.41, ALogP 3.13, HBA 4, HBD 1, PSA 54.56, QED 0.88
Compound (SMILES): C=CC(=O)Nc1ccc(C(=O)Nc2ccc(Nc3ncc4c(n3)N(C)c3ccc(C)cc3C(=O)N4C)cc2)cc1
InChIKey: CPKWRHVMDOSXKE-UHFFFAOYSA-N
Target: Aurora kinase A (SINGLE PROTEIN), Homo sapiens
UniProt: O14965
Assay: Inhibition of Aurora A auto-phosphorylation in human HCT116 cells after 4 hrs by Western blot analysis
Measurement: EC50 = 5.8 nM (pChEMBL 8.239999771118164)
Descriptors: MW 533.59, ALogP 5.26, HBA 7, HBD 3, PSA 119.56, QED 0.29
Compound (SMILES): COc1cc(OC)cc(N(CCCCN)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1
InChIKey: XIRSUXKSURTZHN-UHFFFAOYSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 432.53, ALogP 3.92, HBA 8, HBD 1, PSA 91.32, QED 0.4
Compound (SMILES): COc1cc(OC)cc(N(CCCN2CC[C@H](C#N)C2)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1.Cl
InChIKey: NZPRHAVGOLBEIQ-VEIFNGETSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 497.6, ALogP 4.42, HBA 9, HBD 0, PSA 92.33, QED 0.34
Compound (SMILES): COc1cc(OC)cc(N(C[C@@H](OC(C)=O)C(F)(F)F)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1
InChIKey: HHAMLGNIKIGSCW-XMMPIXPASA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 515.49, ALogP 4.68, HBA 9, HBD 0, PSA 91.6, QED 0.31
Compound (SMILES): COc1cc(CN)cc(N(CC2CC2)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1.Cl
InChIKey: USMMXFMCVGAUGR-UHFFFAOYSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 = 6165.95 nM (pChEMBL 5.210000038146973)
Descriptors: MW 414.51, ALogP 4.05, HBA 7, HBD 1, PSA 82.09, QED 0.49
Compound (SMILES): COc1cc(OC)cc(N(C[C@H](O)C(F)(F)F)c2ccc3ncc(-c4cnn(C(C)C)c4)nc3c2)c1
InChIKey: JXGGHGLZZYBWNG-DEOSSOPVSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 501.51, ALogP 5.15, HBA 8, HBD 1, PSA 85.53, QED 0.36
Compound (SMILES): COc1cc(OC)cc(N(CC2CC2)c2ccc3ncc(-c4cnn(C5CCNCC5)c4)nc3c2)c1
InChIKey: OEIJEWDFQMITII-UHFFFAOYSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 = 5370.32 nM (pChEMBL 5.269999980926514)
Descriptors: MW 484.6, ALogP 4.98, HBA 8, HBD 1, PSA 77.33, QED 0.38
Compound (SMILES): COc1cc(OC)cc(N(CC(O)CN2CCCCC2)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1
InChIKey: PILVYDBBHFTMOU-UHFFFAOYSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 502.62, ALogP 4.03, HBA 9, HBD 1, PSA 88.77, QED 0.37