lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): C=CC(=O)Nc1cc(Nc2ncc(C(=O)OC(C)C)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
InChIKey: AZSRSNUQCUDCGG-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 585.71, ALogP 5.08, HBA 10, HBD 2, PSA 113.85, QED 0.17
Compound (SMILES): C[C@H]1CN(C(=O)CC[C@@]2(C3CC3)NC(=O)NC2=O)CCN1c1cc(F)cc(F)c1
InChIKey: CMLVKUWQFZQPPS-YUNKPMOVSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 in human liver microsomes using testosterone as substrate
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 406.43, ALogP 1.77, HBA 4, HBD 2, PSA 81.75, QED 0.73
Compound (SMILES): CNC[C@@H]1OCCc2ccsc21
InChIKey: ABDDQTDRAHXHOC-QMMMGPOBSA-N
Target: Trace amine-associated receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q96RJ0
Assay: Agonist activity at human TAAR1
Measurement: EC50 = 140 nM (pChEMBL 6.849999904632568)
Descriptors: MW 183.28, ALogP 1.58, HBA 3, HBD 1, PSA 21.26, QED 0.75
Compound (SMILES): Cc1cc(Nc2cc3ncccc3c(N[C@@H]3C[C@H]4CC[C@@H](C3)N4CCC#N)n2)n[nH]1
InChIKey: DADAEARVGOQWHV-OSYLJGHBSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: Inhibition of JAK 1 (unknown origin)
Measurement: IC50 = 10 nM (pChEMBL 8)
Descriptors: MW 402.51, ALogP 3.73, HBA 7, HBD 3, PSA 105.55, QED 0.58
Compound (SMILES): C[C@@H]1Cc2c(ccc3[nH]ncc23)[C@@H](c2ccc(NC3CN(CCCF)C3)cn2)N1CC(F)(F)F
InChIKey: WDHOIABIERMLGY-CMJOXMDJSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 in human liver microsomes
Measurement: IC50 = 2200 nM (pChEMBL 5.659999847412109)
Descriptors: MW 476.52, ALogP 4.31, HBA 5, HBD 2, PSA 60.08, QED 0.5
Compound (SMILES): Cc1cc2c(-c3ccco3)cnc(N[C@@H]3CCN(C)C[C@H]3C(=O)NC3CCCCC3)c2[nH]c1=O
InChIKey: NDEORODKVUYMFQ-NHCUHLMSSA-N
Target: Bromodomain-containing protein 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P25440
Assay: BRD2 BD2 Bromoscan (DiscoverX)
Measurement: Kd = 25118.86 nM (pChEMBL 4.599999904632568)
Descriptors: MW 463.58, ALogP 3.67, HBA 6, HBD 3, PSA 103.26, QED 0.53
Compound (SMILES): CNC(=O)c1cc(C(=O)NC2CC2)cn(Cc2cccc3[nH]ccc23)c1=O
InChIKey: PDCBJZVPIGAEBL-UHFFFAOYSA-N
Target: Voltage-gated inwardly rectifying potassium channel KCNH2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q12809
Assay: Inhibition of human ERG
Measurement: IC50 > 50118.72 nM (pChEMBL 4.300000190734863)
Descriptors: MW 364.41, ALogP 1.63, HBA 4, HBD 3, PSA 95.99, QED 0.64
Compound (SMILES): CCS(=O)(=O)Nc1cc(-c2cn(C)c3c(=O)[nH]ccc23)cc2c1ccn2C(C)(c1ccccn1)c1ccccn1
InChIKey: LMLIBNUOIWAJFC-UHFFFAOYSA-N
Target: Bromodomain-containing protein 4 (SINGLE PROTEIN), Homo sapiens
UniProt: O60885
Assay: Binding affinity to human partial length BRD4 bromodomain 2 long isoform (K333 to E460 residues) expressed in bacterial expression system by BROMOscan assay
Measurement: Kd = 0.33 nM (pChEMBL 9.479999542236328)
Descriptors: MW 552.66, ALogP 4.85, HBA 7, HBD 2, PSA 114.67, QED 0.29
Compound (SMILES): CC1(C)O[C@H]2[C@H](O)[C@H]([C@H]3[C@H](O)[C@H]4OC[C@@H](O4)[C@H]3O)N(CCCCCCn3cc(CNc4ccc(S(N)(=O)=O)cc4)nn3)C[C@H]2O1
InChIKey: MWZLBQWPJOSIAH-DLJZWJNGSA-N
Target: Carbonic anhydrase 13 (SINGLE PROTEIN), Homo sapiens
UniProt: Q8N1Q1
Assay: Inhibition of recombinant human carbonic anhydrase 13 preincubated with enzyme for 15 mins by phenol red dye based stopped flow CO2 hydration assay
Measurement: Ki = 429.1 nM (pChEMBL 6.369999885559082)
Descriptors: MW 652.77, ALogP -0.24, HBA 14, HBD 5, PSA 203.75, QED 0.19
Compound (SMILES): CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
InChIKey: UQTCOSRFOINFNG-FSJACQRISA-N
Target: Neuropeptide Y receptor type 4 (SINGLE PROTEIN), Homo sapiens
UniProt: P50391
Assay: Agonist activity at human Y4R expressed in HEK293T cells co-expressing ARRB1 assessed as induction of beta-arrestin1 recruitment measured for 40 mins by D-luciferin based luminescence assay
Measurement: EC50 = 51 nM (pChEMBL 7.289999961853027)
Descriptors: MW 925.11, ALogP -3.04, HBA 12, HBD 18, PSA 440.77, QED 0.02
Compound (SMILES): C[C@H](Nc1ccc2c(c1)OCCn1cc(N3C(=O)OC[C@H]3C(F)F)nc1-2)C(N)=O
InChIKey: SGEUNORSOZVTOL-CABZTGNLSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: p110alpha (Alpha) PI3K Binding Assay: PI3K Binding assays are intended for determining the biochemical potency of small molecule PI3K inhibitors. The PI3K lipid kinase reaction is performed in the presence of PIP2:3PS lipid substrate (Promega #V1792) and ATP. Following the termination if the kinase reaction, turnover of ATP to ADP by the phosphorylation of the lipid substrate is detected using the Promega ADP-Glo (Promega #V1792) assay. ReactionFinal Kinase ATP PIP2:3PS TimeKinase Source Concentration (uM) (uM) (min.)PI3K alpha Millipore 0.2 nM 40 50 120#14-602-K PI3K beta Promega 0.6 nM 40 50 120#V1751 PI3K delta Millipore 0.25 nM  40 50 120#14-604-K PI3K gamma Millipore 0.4 nM 25 50 120#14-558-KAfter 120 minutes of reaction time, the kinase reaction is terminated. Any ATP remaining after the reaction is depleted, leaving only ADP. Then the Kinase Detection Reagent is added to convert ADP to ATP, which is used in a coupled luciferin/luciferase reaction. The luminescent output is measured and is correlated with kinase activity.
Measurement: Ki = 18.2 nM (pChEMBL 7.739999771118164)
Descriptors: MW 407.38, ALogP 1.82, HBA 7, HBD 2, PSA 111.71, QED 0.78
Compound (SMILES): C=CC(=O)N[C@H]1C=C(C)c2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
InChIKey: MKCYPWYURWOKST-INIZCTEOSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR D770_N771insSVD mutant (unknown origin) expressed in human NCI-H2073 cells preincubated for 2 hrs followed by EGF stimulation for 10 mins by HTRF assay
Measurement: IC50 = 19.95 nM (pChEMBL 7.699999809265137)
Descriptors: MW 396.45, ALogP 3.32, HBA 6, HBD 2, PSA 98.72, QED 0.52
Compound (SMILES): Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)N2CCN(C3COC3)CC2)CC1
InChIKey: QAYHKBLKSXWOEO-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase ATR (SINGLE PROTEIN), Homo sapiens
UniProt: Q13535
Assay: Inhibition Assay: Compounds were screened for their ability to inhibit ATR kinase using a radioactive-phosphate incorporation assay. Assays were carried out in a mixture of 50 mM Tris/HCl (pH 7.5), 10 mM MgCl2 and 1 mM DTT. Final substrate concentrations were 10 μM [γ-33P]ATP (3mCi 33P ATP/mmol ATP, Perkin Elmer) and 800 μM target peptide (ASELPASQPQPFSAKKK) (SEQ ID NO:1).Assays were carried out at 25° C. in the presence of 5 nM full-length ATR. An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 13.5 μL of the stock solution was placed in a 96 well plate followed by addition of 2 μL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 15 μM with 3-fold serial dilutions) in duplicate (final DMSO concentration 7%). The plate was pre-incubated for 10 minutes at 25° C. and the reaction initiated by addition of 15 μL [γ-33P]ATP (final concentration 10 μM).The reaction was stopped after 24 hours by the addition of 30 μL 0.1M phosphoric acid containing 2 mM ATP. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHN0B50) was pretreated with 100 μL 0.2M phosphoric acid prior to the addition of 454 of the stopped assay mixture. The plate was washed with 5×200 μL 0.2M phosphoric acid. After drying, 100 μL Optiphase SuperMix liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
Measurement: Ki = 505 nM (pChEMBL 6.300000190734863)
Descriptors: MW 541.56, ALogP 1, HBA 10, HBD 2, PSA 134.22, QED 0.49
Compound (SMILES): C[C@H]1CN(C(=O)CC[C@@]2(C3CC3)NC(=O)NC2=O)CCN1c1cc(F)cc(F)c1
InChIKey: CMLVKUWQFZQPPS-YUNKPMOVSA-N
Target: A disintegrin and metalloproteinase with thrombospondin motifs 13 (SINGLE PROTEIN), Homo sapiens
UniProt: Q76LX8
Assay: Inhibition of ADAMTS13 (unknown origin)
Measurement: IC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 406.43, ALogP 1.77, HBA 4, HBD 2, PSA 81.75, QED 0.73
Compound (SMILES): CNC[C@@H]1OCCc2ccsc21
InChIKey: ABDDQTDRAHXHOC-QMMMGPOBSA-N
Target: 5-hydroxytryptamine receptor 1A (SINGLE PROTEIN), Homo sapiens
UniProt: P08908
Assay: Agonist activity at 5HT1A (unknown origin)
Measurement: EC50 = 2300 nM (pChEMBL 5.639999866485596)
Descriptors: MW 183.28, ALogP 1.58, HBA 3, HBD 1, PSA 21.26, QED 0.75
Compound (SMILES): Cc1cc(Nc2cc3ncccc3c(N[C@@H]3C[C@H]4CC[C@@H](C3)N4CCC#N)n2)n[nH]1
InChIKey: DADAEARVGOQWHV-OSYLJGHBSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: Inhibition of human recombinant JAK1
Measurement: Ki = 0.1 nM (pChEMBL 10)
Descriptors: MW 402.51, ALogP 3.73, HBA 7, HBD 3, PSA 105.55, QED 0.58
Compound (SMILES): C[C@@H]1Cc2c(ccc3[nH]ncc23)[C@@H](c2ccc(NC3CN(CCCF)C3)cn2)N1CC(F)(F)F
InChIKey: WDHOIABIERMLGY-CMJOXMDJSA-N
Target: Cytochrome P450 2D6 (SINGLE PROTEIN), Homo sapiens
UniProt: P10635
Assay: Inhibition of CYP2D6 in human liver microsomes
Measurement: IC50 = 4300 nM (pChEMBL 5.369999885559082)
Descriptors: MW 476.52, ALogP 4.31, HBA 5, HBD 2, PSA 60.08, QED 0.5
Compound (SMILES): Cc1cc2c(-c3ccco3)cnc(N[C@@H]3CCN(C)C[C@H]3C(=O)NC3CCCCC3)c2[nH]c1=O
InChIKey: NDEORODKVUYMFQ-NHCUHLMSSA-N
Target: Bromodomain-containing protein 3 (SINGLE PROTEIN), Homo sapiens
UniProt: Q15059
Assay: BRD3 BD1 Bromoscan (DiscoverX)
Measurement: Kd = 15.85 nM (pChEMBL 7.800000190734863)
Descriptors: MW 463.58, ALogP 3.67, HBA 6, HBD 3, PSA 103.26, QED 0.53
Compound (SMILES): CNC(=O)c1cc(C(=O)NC2CC2)cn(Cc2cccc3[nH]ccc23)c1=O
InChIKey: PDCBJZVPIGAEBL-UHFFFAOYSA-N
Target: Bile salt export pump (SINGLE PROTEIN), Homo sapiens
UniProt: O95342
Assay: Inhibition of BSEP (unknown origin)
Measurement: IC50 = 50118.72 nM (pChEMBL 4.300000190734863)
Descriptors: MW 364.41, ALogP 1.63, HBA 4, HBD 3, PSA 95.99, QED 0.64
Compound (SMILES): CCS(=O)(=O)Nc1cc(-c2cn(C)c3c(=O)[nH]ccc23)cc2c1ccn2C(C)(c1ccccn1)c1ccccn1
InChIKey: LMLIBNUOIWAJFC-UHFFFAOYSA-N
Target: Bromodomain-containing protein 4 (SINGLE PROTEIN), Homo sapiens
UniProt: O60885
Assay: Binding affinity to human partial length BRD4 long isoform bromodomain 1 and 2 (N44 to E460 residues) expressed in bacterial expression system by BROMOscan assay by BROMOscan assay
Measurement: Kd = 0.29 nM (pChEMBL 9.539999961853027)
Descriptors: MW 552.66, ALogP 4.85, HBA 7, HBD 2, PSA 114.67, QED 0.29
Compound (SMILES): CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
InChIKey: UQTCOSRFOINFNG-FSJACQRISA-N
Target: Neuropeptide Y receptor type 4 (SINGLE PROTEIN), Homo sapiens
UniProt: P50391
Assay: Agonist activity at human Y4R expressed in HEK293T cells co-expressing ARRB2 assessed as induction of beta-arrestin2 recruitment measured for 40 mins by D-luciferin based luminescence assay
Measurement: EC50 = 38.02 nM (pChEMBL 7.420000076293945)
Descriptors: MW 925.11, ALogP -3.04, HBA 12, HBD 18, PSA 440.77, QED 0.02
Compound (SMILES): C[C@H](Nc1ccc2c(c1)OCCn1cc(N3C(=O)OC[C@H]3C(F)F)nc1-2)C(N)=O
InChIKey: SGEUNORSOZVTOL-CABZTGNLSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Biochemical Inhibition Assay: The biochemical inhibition of four PI3K isoforms by the Formula I compounds of Table 1. In addition, two clinically tested PI3K compounds, taselisib and pictilisib are included as comparators. The representative compounds of the invention exhibit strong activity against PI3Kα, and exhibit significantly enhanced selectivity relative to the other isoforms PI3Kβ, PI3Kδ, and PI3Kγ when compared to taselisib (GDC-0032) and pictilisib (GDC-0941). In particular, the selectivity ratios in the second from the right column of Table 2A show that each Formula I compounds 101-107 has a PI3K alpha to delta selectivity ratio far higher than taselisib or pictilisib. In fact, both taselisib and pictilisib have stronger activity against PI3K delta than against PI3K alpha, i.e. their selectivity ratios are less than 1. The selectivity ratios of Formula I compound 101-107 range from 301-fold to 634-fold.
Measurement: Ki = 0.034 nM (pChEMBL 10.470000267028809)
Descriptors: MW 407.38, ALogP 1.82, HBA 7, HBD 2, PSA 111.71, QED 0.78
Compound (SMILES): C=CC(=O)N[C@H]1C=C(C)c2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
InChIKey: MKCYPWYURWOKST-INIZCTEOSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR D770_N771insNPG mutant (unknown origin) by HTRF assay
Measurement: IC50 = 5.012 nM (pChEMBL 8.300000190734863)
Descriptors: MW 396.45, ALogP 3.32, HBA 6, HBD 2, PSA 98.72, QED 0.52
Compound (SMILES): Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)N2CCN(C3COC3)CC2)CC1
InChIKey: QAYHKBLKSXWOEO-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase ATR (SINGLE PROTEIN), Homo sapiens
UniProt: Q13535
Assay: Inhibition Assay: Compounds were screened for their ability to inhibit ATR kinase using a radioactive-phosphate incorporation assay. Assays were carried out in a mixture of 50 mM Tris/HCl (pH 7.5), 10 mM MgCl2 and 1 mM DTT. Final substrate concentrations were 10 μM [γ-33P]ATP (3mCi 33P ATP/mmol ATP, Perkin Elmer) and 800 μM target peptide (ASELPASQPQPFSAKKK) (SEQ ID NO:1).Assays were carried out at 25° C. in the presence of 5 nM full-length ATR. An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 13.5 μL of the stock solution was placed in a 96 well plate followed by addition of 2 μL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 15 μM with 3-fold serial dilutions) in duplicate (final DMSO concentration 7%). The plate was pre-incubated for 10 minutes at 25° C. and the reaction initiated by addition of 15 μL [γ-33P]ATP (final concentration 10 μM).The reaction was stopped after 24 hours by the addition of 30 μL 0.1M phosphoric acid containing 2 mM ATP. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no. MAPHN0B50) was pretreated with 100 μL 0.2M phosphoric acid prior to the addition of 454 of the stopped assay mixture. The plate was washed with 5×200 μL 0.2M phosphoric acid. After drying, 100 μL Optiphase SuperMix liquid scintillation cocktail (Perkin Elmer) was added to the well prior to scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
Measurement: Ki < 10 nM (pChEMBL 8)
Descriptors: MW 541.56, ALogP 1, HBA 10, HBD 2, PSA 134.22, QED 0.49
Compound (SMILES): C=CC(=O)Nc1cc(Nc2ncc(C(=O)OC(C)C)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
InChIKey: AZSRSNUQCUDCGG-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 585.71, ALogP 5.08, HBA 10, HBD 2, PSA 113.85, QED 0.17
Compound (SMILES): C[C@H]1CN(C(=O)CC[C@@]2(C3CC3)NC(=O)NC2=O)CCN1c1cc(F)cc(F)c1
InChIKey: CMLVKUWQFZQPPS-YUNKPMOVSA-N
Target: A disintegrin and metalloproteinase with thrombospondin motifs 5 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UNA0
Assay: In Vitro Assay: ADAMTS-5:Protocol 2: The basis for the assay is the cleavage of the substrate TBIS-1 (5 FAM-TEGEARGSVILLK (5TAMRA)K-NH2) (SEQ ID No 2) by human ADAMTS-5.For the dose response (10 point), 4 μL of a dilution series of compound (2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in 10 in water, corresponding to a final highest concentration of 20 μM), is transferred to 384 well Fluotrac 200 plate (Greiner, cat #781076) and incubated at room temperature for 30 min with a 26 μL buffer solution (50 mM Hepes pH7.5, 100 mM NaCl, 5 mM CaCl2, 0.1% CHAPS 1) containing hADAMTS-5 (1 ng/μL, affinity purified, followed by overnight digestion of 6His tag by thrombin and dialysis) (it will be appreciated by the skilled person that the potency read out is independent of the enzyme concentration).The reaction is initiated by adding to the assay plate TBIS-1 (10 μL, 4.5 μM, Anaspec) in the same buffer.Finally, the fluorescence is read on the Envision (Perkin Elmer) after an incubation of 45 min at 37° C. (Excitation 485 nm, emission 530).
Measurement: IC50 = 20 nM (pChEMBL 7.699999809265137)
Descriptors: MW 406.43, ALogP 1.77, HBA 4, HBD 2, PSA 81.75, QED 0.73
Compound (SMILES): CNC[C@@H]1OCCc2ccsc21
InChIKey: ABDDQTDRAHXHOC-QMMMGPOBSA-N
Target: D(2) dopamine receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P14416
Assay: Agonist activity at D2 (unknown origin) by beta-arrestin recruitment assay
Measurement: IC50 = 24000 nM (pChEMBL 4.619999885559082)
Descriptors: MW 183.28, ALogP 1.58, HBA 3, HBD 1, PSA 21.26, QED 0.75
Compound (SMILES): Cc1cc(Nc2cc3ncccc3c(N[C@@H]3C[C@H]4CC[C@@H](C3)N4CCC#N)n2)n[nH]1
InChIKey: DADAEARVGOQWHV-OSYLJGHBSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: Inhibition of human recombinant JAK2
Measurement: Ki = 0.1 nM (pChEMBL 10)
Descriptors: MW 402.51, ALogP 3.73, HBA 7, HBD 3, PSA 105.55, QED 0.58
Compound (SMILES): C[C@@H]1Cc2c(ccc3[nH]ncc23)[C@@H](c2ccc(NC3CN(CCCF)C3)cn2)N1CC(F)(F)F
InChIKey: WDHOIABIERMLGY-CMJOXMDJSA-N
Target: Estrogen receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P03372
Assay: Displacement of fluorescent labelled fluormone ES2 from human recombinant GST tagged ER alpha LBD ( 282 to 595 residues) expressed in baculovirus infected insect cells incubate for 20 mins measured after 1 hr by TR-FRET Lanthascreen assay
Measurement: IC50 = 2.512 nM (pChEMBL 8.600000381469727)
Descriptors: MW 476.52, ALogP 4.31, HBA 5, HBD 2, PSA 60.08, QED 0.5
Compound (SMILES): Cc1cc2c(-c3ccco3)cnc(N[C@@H]3CCN(C)C[C@H]3C(=O)NC3CCCCC3)c2[nH]c1=O
InChIKey: NDEORODKVUYMFQ-NHCUHLMSSA-N
Target: Bromodomain-containing protein 3 (SINGLE PROTEIN), Homo sapiens
UniProt: Q15059
Assay: BRD3 BD2 Bromoscan (DiscoverX)
Measurement: Kd = 19952.62 nM (pChEMBL 4.699999809265137)
Descriptors: MW 463.58, ALogP 3.67, HBA 6, HBD 3, PSA 103.26, QED 0.53
Compound (SMILES): CCS(=O)(=O)Nc1cc(-c2cn(C)c3c(=O)[nH]ccc23)cc2c1ccn2C(C)(c1ccccn1)c1ccccn1
InChIKey: LMLIBNUOIWAJFC-UHFFFAOYSA-N
Target: Bromodomain testis-specific protein (SINGLE PROTEIN), Homo sapiens
UniProt: Q58F21
Assay: Binding affinity to human partial length BRDT bromodomain 1 (N21 to E137 residues) expressed in bacterial expression system by BROMOscan assay
Measurement: Kd = 0.14 nM (pChEMBL 9.850000381469727)
Descriptors: MW 552.66, ALogP 4.85, HBA 7, HBD 2, PSA 114.67, QED 0.29
Compound (SMILES): CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
InChIKey: UQTCOSRFOINFNG-FSJACQRISA-N
Target: Neuropeptide Y receptor type 4 (SINGLE PROTEIN), Homo sapiens
UniProt: P50391
Assay: Agonist activity at human Y4R expressed in HEK293T cells co-expressing ARRB2 assessed as induction of beta-arrestin2 recruitment measured for 40 mins by D-luciferin based luminescence assay
Measurement: EC50 = 38 nM (pChEMBL 7.420000076293945)
Descriptors: MW 925.11, ALogP -3.04, HBA 12, HBD 18, PSA 440.77, QED 0.02
Compound (SMILES): C[C@H](Nc1ccc2c(c1)OCCn1cc(N3C(=O)OC[C@H]3C(F)F)nc1-2)C(N)=O
InChIKey: SGEUNORSOZVTOL-CABZTGNLSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42338
Assay: Biochemical Inhibition Assay: The biochemical inhibition of four PI3K isoforms by the Formula I compounds of Table 1. In addition, two clinically tested PI3K compounds, taselisib and pictilisib are included as comparators. The representative compounds of the invention exhibit strong activity against PI3Kα, and exhibit significantly enhanced selectivity relative to the other isoforms PI3Kβ, PI3Kδ, and PI3Kγ when compared to taselisib (GDC-0032) and pictilisib (GDC-0941). In particular, the selectivity ratios in the second from the right column of Table 2A show that each Formula I compounds 101-107 has a PI3K alpha to delta selectivity ratio far higher than taselisib or pictilisib. In fact, both taselisib and pictilisib have stronger activity against PI3K delta than against PI3K alpha, i.e. their selectivity ratios are less than 1. The selectivity ratios of Formula I compound 101-107 range from 301-fold to 634-fold.
Measurement: Ki = 99.7 nM (pChEMBL 7)
Descriptors: MW 407.38, ALogP 1.82, HBA 7, HBD 2, PSA 111.71, QED 0.78
Compound (SMILES): C=CC(=O)N[C@H]1C=C(C)c2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
InChIKey: MKCYPWYURWOKST-INIZCTEOSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR D770_N771insSVD mutant (unknown origin) expressed in human NCI-H2073 cells by ELISA
Measurement: IC50 = 63.1 nM (pChEMBL 7.199999809265137)
Descriptors: MW 396.45, ALogP 3.32, HBA 6, HBD 2, PSA 98.72, QED 0.52
Compound (SMILES): Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)N2CCN(C3COC3)CC2)CC1
InChIKey: QAYHKBLKSXWOEO-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase ATR (SINGLE PROTEIN), Homo sapiens
UniProt: Q13535
Assay: Inhibition Assay: Table 5: Compounds were screened for their ability to inhibit ATR kinase using a radioactive-phosphate incorporation assay. Assays were carried out in a mixture of 50 mM Tris/HCl (pH 7.5), 10 mM MgCl2 and 1 mM DTT. Final substrate concentrations were 10 μM [y-33P]ATP (3 mCi 33P ATP/mmol ATP, Perkin Elmer) and 800 μM target peptide(ASELPASQPQPFSAKKK) (SEQ ID NO:1).Assays were carried out at 25° C. in the presence of 5 nM full-length ATR. An assay stock buffer solution was prepared containing all of the reagents listed above, with the exception of ATP and the test compound of interest. 13.5 μL of the stock solution was placed in a 96 well plate followed by addition of 2 μL of DMSO stock containing serial dilutions of the test compound (typically starting from a final concentration of 15 μM with 3-fold serial dilutions) in duplicate (final DMSO concentration 7%). The plate was pre-incubated for 10 minutes at 25° C. and the reaction initiated by addition of 15 μL [γ-33P]ATP (final concentration 10 μM).
Measurement: Ki = 550 nM (pChEMBL 6.260000228881836)
Descriptors: MW 541.56, ALogP 1, HBA 10, HBD 2, PSA 134.22, QED 0.49
Compound (SMILES): C=CC(=O)Nc1cc(Nc2ncc(C(=O)OC(C)C)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
InChIKey: AZSRSNUQCUDCGG-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: EGFR Exon 21 L858R and Exon 20 T790M Concurrent Mutations: A compound's ability in selectively inhibiting EGFR L858R and T790M concurrent mutations can be assessed using Ba/F3 cells, a murine pro-B cell line, which have been transduced with EGFR L858R and T790M double mutations. An expression vector, pLVX-IRES puro (Clontech) coding for human EGFR L858R and T790M double mutation, was transfected into HEK293 cells by the Trans-Lentiviral ORF Packaging System (Thermo Scientific), to produce virus encoding EGFR L858R and T790M double 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 L858R and T790M double mutation virus and subsequently selected by puromycin (Life Technology) selection and IL-3 depletion. Ba/F3 cells expressing EGFR L858R and T790M double mutation (named Ba/F3-EGFR L858R/T790M) can proliferate in the absence of IL-3. The anti-proliferative activity of compounds was determined as follows: BaF3-EGFR L858R/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 585.71, ALogP 5.08, HBA 10, HBD 2, PSA 113.85, QED 0.17
Compound (SMILES): C[C@H]1CN(C(=O)CC[C@@]2(C3CC3)NC(=O)NC2=O)CCN1c1cc(F)cc(F)c1
InChIKey: CMLVKUWQFZQPPS-YUNKPMOVSA-N
Target: Disintegrin and metalloproteinase domain-containing protein 17 (SINGLE PROTEIN), Homo sapiens
UniProt: P78536
Assay: In Vitro Assay: TACE:The basis for the assay is the cleavage of the substrate 5FAM-LAQAVRSSSRK-5TAMRA (SEQ ID No 3) (Anaspec, custom 34891) by human TACE (R&D SYSTEMS INC., Cat #930-ADB).For the dose response (10 point), 4 μL of a dilution series of compound (2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in 10 in water, corresponding to a final highest concentration of 20 μM), is transferred to 384 well Fluotrac 200 plate (Greiner, cat #781076) and incubated at room temperature for 30 min with a 26 μL buffer solution (25 mM Tris pH8.0, 2.5 μM ZnCl2, 0.01% CHAPS) containing TACE (0.05 ng/μL) (it will be appreciated by the skilled person that the potency read out is independent of the enzyme concentration).The reaction is initiated by adding to the assay plate 5FAM-LAQAVRSSSRK-5TAMRA (5 L, 5 μM, Anaspec) in the same buffer.Finally, the fluorescence is read on the Envision (Perkin Elmer) after an incubation of 75 min at room temperature (Excitation 485 nm, Emission 530).
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 406.43, ALogP 1.77, HBA 4, HBD 2, PSA 81.75, QED 0.73
Compound (SMILES): CNC[C@@H]1OCCc2ccsc21
InChIKey: ABDDQTDRAHXHOC-QMMMGPOBSA-N
Target: D(2) dopamine receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P14416
Assay: Agonist activity at D2 (unknown origin) by HTRF assay
Measurement: EC50 = 10000 nM (pChEMBL 5)
Descriptors: MW 183.28, ALogP 1.58, HBA 3, HBD 1, PSA 21.26, QED 0.75
Compound (SMILES): Cc1cc(Nc2cc3ncccc3c(N[C@@H]3C[C@H]4CC[C@@H](C3)N4CCC#N)n2)n[nH]1
InChIKey: DADAEARVGOQWHV-OSYLJGHBSA-N
Target: Tyrosine-protein kinase JAK3 (SINGLE PROTEIN), Homo sapiens
UniProt: P52333
Assay: Inhibition of human recombinant JAK3
Measurement: Ki = 1.585 nM (pChEMBL 8.800000190734863)
Descriptors: MW 402.51, ALogP 3.73, HBA 7, HBD 3, PSA 105.55, QED 0.58
Compound (SMILES): C[C@@H]1Cc2c(ccc3[nH]ncc23)[C@@H](c2ccc(NC3CN(CCCF)C3)cn2)N1CC(F)(F)F
InChIKey: WDHOIABIERMLGY-CMJOXMDJSA-N
Target: Estrogen receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P03372
Assay: Induction of ERalpha degradation in human MCF7 cells incubated for 18 to 22 hrs by immuno-fluorescence assay
Measurement: IC50 = 0.1585 nM (pChEMBL 9.800000190734863)
Descriptors: MW 476.52, ALogP 4.31, HBA 5, HBD 2, PSA 60.08, QED 0.5
Compound (SMILES): Cc1cc2c(-c3ccco3)cnc(N[C@@H]3CCN(C)C[C@H]3C(=O)NC3CCCCC3)c2[nH]c1=O
InChIKey: NDEORODKVUYMFQ-NHCUHLMSSA-N
Target: Bromodomain-containing protein 4 (SINGLE PROTEIN), Homo sapiens
UniProt: O60885
Assay: BRD4 BD1 Bromoscan (DiscoverX)
Measurement: Kd = 19.95 nM (pChEMBL 7.699999809265137)
Descriptors: MW 463.58, ALogP 3.67, HBA 6, HBD 3, PSA 103.26, QED 0.53
Compound (SMILES): CCS(=O)(=O)Nc1cc(-c2cn(C)c3c(=O)[nH]ccc23)cc2c1ccn2C(C)(c1ccccn1)c1ccccn1
InChIKey: LMLIBNUOIWAJFC-UHFFFAOYSA-N
Target: Bromodomain testis-specific protein (SINGLE PROTEIN), Homo sapiens
UniProt: Q58F21
Assay: Binding affinity to human partial length BRDT bromodomain 2 (K250 to E382 residues) expressed in bacterial expression system by BROMOscan assay
Measurement: Kd = 0.23 nM (pChEMBL 9.640000343322754)
Descriptors: MW 552.66, ALogP 4.85, HBA 7, HBD 2, PSA 114.67, QED 0.29
Compound (SMILES): CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
InChIKey: UQTCOSRFOINFNG-FSJACQRISA-N
Target: Neuropeptide Y receptor type 4 (SINGLE PROTEIN), Homo sapiens
UniProt: P50391
Assay: Agonist activity at human Y4 receptor expressed in CHO cells co-expressing Gqi5-mtAEQ assessed as intracellular calcium mobilization measured for 43 secs in presence of coelenterazine by aequorin-reporter gene based luminescence assay
Measurement: EC50 = 102.33 nM (pChEMBL 6.989999771118164)
Descriptors: MW 925.11, ALogP -3.04, HBA 12, HBD 18, PSA 440.77, QED 0.02
Compound (SMILES): C[C@H](Nc1ccc2c(c1)OCCn1cc(N3C(=O)OC[C@H]3C(F)F)nc1-2)C(N)=O
InChIKey: SGEUNORSOZVTOL-CABZTGNLSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Biochemical Inhibition Assay: The biochemical inhibition of four PI3K isoforms by the Formula I compounds of Table 1. In addition, two clinically tested PI3K compounds, taselisib and pictilisib are included as comparators. The representative compounds of the invention exhibit strong activity against PI3Kα, and exhibit significantly enhanced selectivity relative to the other isoforms PI3Kβ, PI3Kδ, and PI3Kγ when compared to taselisib (GDC-0032) and pictilisib (GDC-0941). In particular, the selectivity ratios in the second from the right column of Table 2A show that each Formula I compounds 101-107 has a PI3K alpha to delta selectivity ratio far higher than taselisib or pictilisib. In fact, both taselisib and pictilisib have stronger activity against PI3K delta than against PI3K alpha, i.e. their selectivity ratios are less than 1. The selectivity ratios of Formula I compound 101-107 range from 301-fold to 634-fold.
Measurement: Ki = 12.2 nM (pChEMBL 7.909999847412109)
Descriptors: MW 407.38, ALogP 1.82, HBA 7, HBD 2, PSA 111.71, QED 0.78
Compound (SMILES): C=CC(=O)Nc1cc(Nc2ncc(C(=O)OC(C)C)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
InChIKey: AZSRSNUQCUDCGG-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: HER2 Exon 20 YVMA Insertion Mutation: A compound's ability in selectively inhibiting Her2 exon 20 YVMA insertion mutations can be assessed using Ba/F3 cells, a murine pro-B cell line, which have been transduced with Her2 Exon20 YVMA insertions. An expression vector, pLVX-IRES puro (Clontech) coding for human EGFR exon 20 insertions YVMA (A775_G776ins YVMA), 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 Her2 Exon20 YVMA insertions (named Ba/F3-Her2 Exon20 YVMA) can proliferate in the absence of IL-3. The anti-proliferative activity of compounds was determined as follows: BaF3-Her2 Exon20 YVMA 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 585.71, ALogP 5.08, HBA 10, HBD 2, PSA 113.85, QED 0.17
Compound (SMILES): C[C@H]1CN(C(=O)CC[C@@]2(C3CC3)NC(=O)NC2=O)CCN1c1cc(F)cc(F)c1
InChIKey: CMLVKUWQFZQPPS-YUNKPMOVSA-N
Target: Interstitial collagenase (SINGLE PROTEIN), Homo sapiens
UniProt: P03956
Assay: In Vitro Assay: Inhibition of the proteases human MMP1 was determined at REACTION BIOLOGY (Reaction Biology Corp. 1 Great Valley Parkway, Suite 2 Malvern, Pa. 19355, USA) in fluorescent based biochemical assays. The protease activities were monitored as a time-course measurement of the increase in fluorescence signal from fluorescently-labeled peptide substrates, and initial linear portion of slope (signal/min) was analyzed.
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 406.43, ALogP 1.77, HBA 4, HBD 2, PSA 81.75, QED 0.73
Compound (SMILES): Cc1cc(Nc2cc3ncccc3c(N[C@@H]3C[C@H]4CC[C@@H](C3)N4CCC#N)n2)n[nH]1
InChIKey: DADAEARVGOQWHV-OSYLJGHBSA-N
Target: Non-receptor tyrosine-protein kinase TYK2 (SINGLE PROTEIN), Homo sapiens
UniProt: P29597
Assay: Inhibition of human recombinant TYK2
Measurement: Ki = 0.3162 nM (pChEMBL 9.5)
Descriptors: MW 402.51, ALogP 3.73, HBA 7, HBD 3, PSA 105.55, QED 0.58
Compound (SMILES): C[C@@H]1Cc2c(ccc3[nH]ncc23)[C@@H](c2ccc(NC3CN(CCCF)C3)cn2)N1CC(F)(F)F
InChIKey: WDHOIABIERMLGY-CMJOXMDJSA-N
Target: Estrogen receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P03372
Assay: Induction of ERalpha degradation in human MCF7
Measurement: EC50 < 1 nM (pChEMBL 9)
Descriptors: MW 476.52, ALogP 4.31, HBA 5, HBD 2, PSA 60.08, QED 0.5
Compound (SMILES): Cc1cc2c(-c3ccco3)cnc(N[C@@H]3CCN(C)C[C@H]3C(=O)NC3CCCCC3)c2[nH]c1=O
InChIKey: NDEORODKVUYMFQ-NHCUHLMSSA-N
Target: Bromodomain-containing protein 4 (SINGLE PROTEIN), Homo sapiens
UniProt: O60885
Assay: BRD4 BD2 Bromoscan (DiscoverX)
Measurement: Kd = 31622.78 nM (pChEMBL 4.5)
Descriptors: MW 463.58, ALogP 3.67, HBA 6, HBD 3, PSA 103.26, QED 0.53
Compound (SMILES): CCS(=O)(=O)Nc1cc(-c2cn(C)c3c(=O)[nH]ccc23)cc2c1ccn2C(C)(c1ccccn1)c1ccccn1
InChIKey: LMLIBNUOIWAJFC-UHFFFAOYSA-N
Target: Bromodomain testis-specific protein (SINGLE PROTEIN), Homo sapiens
UniProt: Q58F21
Assay: Binding affinity to human partial length BRDT isoform b bromodomain 1 and 2 (N21 to E382 residues) expressed in bacterial expression system by BROMOscan assay
Measurement: Kd = 1.4 nM (pChEMBL 8.850000381469727)
Descriptors: MW 552.66, ALogP 4.85, HBA 7, HBD 2, PSA 114.67, QED 0.29
Compound (SMILES): CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O
InChIKey: UQTCOSRFOINFNG-FSJACQRISA-N
Target: Neuropeptide Y receptor type 4 (SINGLE PROTEIN), Homo sapiens
UniProt: P50391
Assay: Agonist activity at human Y4 receptor expressed in CHO cells co-expressing Gqi5-mtAEQ assessed as intracellular calcium mobilization measured for 43 secs in presence of coelenterazine by aequorin-reporter gene based luminescence assay
Measurement: EC50 = 100 nM (pChEMBL 7)
Descriptors: MW 925.11, ALogP -3.04, HBA 12, HBD 18, PSA 440.77, QED 0.02
Compound (SMILES): C[C@H](Nc1ccc2c(c1)OCCn1cc(N3C(=O)OC[C@H]3C(F)F)nc1-2)C(N)=O
InChIKey: SGEUNORSOZVTOL-CABZTGNLSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (SINGLE PROTEIN), Homo sapiens
UniProt: O00329
Assay: Biochemical Inhibition Assay: The biochemical inhibition of four PI3K isoforms by the Formula I compounds of Table 1. In addition, two clinically tested PI3K compounds, taselisib and pictilisib are included as comparators. The representative compounds of the invention exhibit strong activity against PI3Kα, and exhibit significantly enhanced selectivity relative to the other isoforms PI3Kβ, PI3Kδ, and PI3Kγ when compared to taselisib (GDC-0032) and pictilisib (GDC-0941). In particular, the selectivity ratios in the second from the right column of Table 2A show that each Formula I compounds 101-107 has a PI3K alpha to delta selectivity ratio far higher than taselisib or pictilisib. In fact, both taselisib and pictilisib have stronger activity against PI3K delta than against PI3K alpha, i.e. their selectivity ratios are less than 1. The selectivity ratios of Formula I compound 101-107 range from 301-fold to 634-fold.
Measurement: Ki = 18.2 nM (pChEMBL 7.739999771118164)
Descriptors: MW 407.38, ALogP 1.82, HBA 7, HBD 2, PSA 111.71, QED 0.78
Compound (SMILES): C=CC(=O)Nc1cc(Nc2ncc(C(=O)OC(C)C)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
InChIKey: AZSRSNUQCUDCGG-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR D770_N771insNPG mutant (unknown origin) by HTRF assay
Measurement: IC50 = 7.943 nM (pChEMBL 8.100000381469727)
Descriptors: MW 585.71, ALogP 5.08, HBA 10, HBD 2, PSA 113.85, QED 0.17
Compound (SMILES): C[C@H]1CN(C(=O)CC[C@@]2(C3CC3)NC(=O)NC2=O)CCN1c1cc(F)cc(F)c1
InChIKey: CMLVKUWQFZQPPS-YUNKPMOVSA-N
Target: 72 kDa type IV collagenase (SINGLE PROTEIN), Homo sapiens
UniProt: P08253
Assay: In Vitro Assay: MMP2: Protocol 2: The basis for the assay is the cleavage of the substrate 390 MMP FRET substrate I (Anaspec, Catalog n#: AS-27076) by human MMP2 (R&D SYSTEMS INC., Cat #902-MP).For the dose response (10 point), 4 μL of a dilution series of compound (2 mM highest concentration, 1/5 dilution in DMSO further diluted 1 in 10 in water, corresponding to a final highest concentration of 20 μM), is transferred to 384 well Fluotrac 200 plate (Greiner, cat #781076) and incubated at room temperature for 30 min with a 26 μL buffer solution (45 mM Tris pH 7.5, 9 mM CaCl2, 135 mM NaCl, 0.045% Brij35) containing MMP2 (0.03 ng/L) (it will be appreciated by the skilled person that the potency read out is independent of the enzyme concentration).The reaction is initiated by adding to the assay plate 390 MMP FRET substrate I (10 μL, 2.5 μM, Anaspec) in the same buffer.Finally, the fluorescence is read on the Envision (Perkin Elmer) after an incubation of 30 min at room temperature (Excitation 485 nm, Emission 530).
Measurement: IC50 = 123 nM (pChEMBL 6.909999847412109)
Descriptors: MW 406.43, ALogP 1.77, HBA 4, HBD 2, PSA 81.75, QED 0.73
Compound (SMILES): C[C@@H]1Cc2c(ccc3[nH]ncc23)[C@@H](c2ccc(NC3CN(CCCF)C3)cn2)N1CC(F)(F)F
InChIKey: WDHOIABIERMLGY-CMJOXMDJSA-N
Target: Estrogen receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P03372
Assay: Binding Assay: The assay was performed as follows with all reagent additions carried out using the Beckman Coulter BioRAPTR FRD microfluidic workstation:1. Acoustic dispense 120 nL of the test compound into a black low volume 384 well assay plates.2. Prepare 1×ER alpha-LBD/Tb-antiGST Ab in ES2 screening buffer and incubate for 15 minutes.3. Dispense 6 μL of the 1×AR-LBD/Tb-anti-GST Ab reagent into each well of the assay plate followed by 6 μL of Fluorophore reagent into each well of the assay plate4. Cover the assay plate to protect the reagents from light and evaporation, and incubate at room temperature for 4 hours.5. Excite at 337 nm and measure the fluorescent emission signal of each well at 490 nm and 520 nm using the BMG PheraSTAR.
Measurement: IC50 = 2.4 nM (pChEMBL 8.619999885559082)
Descriptors: MW 476.52, ALogP 4.31, HBA 5, HBD 2, PSA 60.08, QED 0.5
Compound (SMILES): Cc1cc2c(-c3ccco3)cnc(N[C@@H]3CCN(C)C[C@H]3C(=O)NC3CCCCC3)c2[nH]c1=O
InChIKey: NDEORODKVUYMFQ-NHCUHLMSSA-N
Target: Bromodomain testis-specific protein (SINGLE PROTEIN), Homo sapiens
UniProt: Q58F21
Assay: BRDT BD1 Bromoscan (DiscoverX)
Measurement: Kd = 19.95 nM (pChEMBL 7.699999809265137)
Descriptors: MW 463.58, ALogP 3.67, HBA 6, HBD 3, PSA 103.26, QED 0.53
Compound (SMILES): CCS(=O)(=O)Nc1cc(-c2cn(C)c3c(=O)[nH]ccc23)cc2c1ccn2C(C)(c1ccccn1)c1ccccn1
InChIKey: LMLIBNUOIWAJFC-UHFFFAOYSA-N
Target: ATPase family AAA domain-containing protein 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q6PL18
Assay: Binding affinity to human partial length ATAD2A (Q981 to R1108 residues) expressed in bacterial expression system by BROMOscan assay
Measurement: Kd > 10000 nM (pChEMBL 5)
Descriptors: MW 552.66, ALogP 4.85, HBA 7, HBD 2, PSA 114.67, QED 0.29
Compound (SMILES): C=CC(=O)Nc1cc(Nc2ncc(C(=O)OC(C)C)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
InChIKey: AZSRSNUQCUDCGG-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of EGFR D770_N771insSVD mutant (unknown origin) expressed in human NCI-H2073 cells by ELISA
Measurement: IC50 = 19.95 nM (pChEMBL 7.699999809265137)
Descriptors: MW 585.71, ALogP 5.08, HBA 10, HBD 2, PSA 113.85, QED 0.17
Compound (SMILES): C[C@H]1CN(C(=O)CC[C@@]2(C3CC3)NC(=O)NC2=O)CCN1c1cc(F)cc(F)c1
InChIKey: CMLVKUWQFZQPPS-YUNKPMOVSA-N
Target: Collagenase 3 (SINGLE PROTEIN), Homo sapiens
UniProt: P45452
Assay: In Vitro Assay: MMP-13:The basis for the assay is the cleavage of the substrate 390 MMP FRET Substrate I (Anaspec Cat # AS-27076) by human MMP13 (Chemicon, Cat #CC068).For the dose response (10 point), 4 μL of a dilution series of compound (20 μM highest concentration, 1/5 dilution in water), is transferred to 384 well Fluotrac 200 plate (Greiner, cat #781076) and incubated at room temperature for 30 min with a 26 μL buffer solution (50 mM Tris pH7.5, 150 mM NaCl, 10 mM CaCl2, 0.05% CHAPS, 5 μM ZnCl2) containing MMP13 (0.01 ng/IL) (it will be appreciated by the skilled person that the potency read out is independent of the enzyme concentration). Human MMP13 is preactivated by incubated the enzyme in the same buffer complemented with 1 mM freshly prepared p-Aminophenylmercuric acetate (AMPA) for 1 hour at 37° C.The reaction is initiated by adding to the assay plate 390 MMP FRET Substrate I (10 μL, 2.5 μM) in the same buffer.Finally, the fluorescence is read on the Envision (Perkin Elmer) after an incubation of 45 min at room temperature (Excitation 485 nm, Emission 530).
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 406.43, ALogP 1.77, HBA 4, HBD 2, PSA 81.75, QED 0.73