lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): Cc1coc(CC(=O)Nc2cc([C@H]3CC[C@@H](OC(=O)N[C@@H](C)CC(F)(F)F)C3)[nH]n2)n1
InChIKey: RPHJDZIFZCDRGC-WCFLWFBJSA-N
Target: Cyclin-dependent kinase 2/cyclin E1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24941
Assay: Biochemical Assay: The purpose of CDK2/Cyclin E1 assay is to evaluate the inhibition (% inhibition, Kiapp and Ki values) of small molecule inhibitors by using a fluorescence-based microfluidic mobility shift assay. CDK2/Cyclin E1 full length catalyzes the production of ADP from ATP that accompanies the phosphoryl transfer to the substrate peptide FL-Peptide-18 (5-FAM-QSPKKG-CONH2, CPC Scientific, Sunnyvale, Calif.) (SEQ ID NO:1). The mobility shift assay electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product) following the kinase reaction. Both substrate and product are measured and the ratio of these values is used to generate % conversion of substrate to product by the LabChip EZ Reader. Wild-type CDK2/wild-type full length Cyclin E1 enzyme complex was produced in-house (baculoviral expression, LJIC-2080/LJIC-2103) and phosphorylated by CDK7/Cyclin H1/Matl enzyme complex with CDK2:CDK7 ratio of 50:1 (concentration mg/mL) in the presence of 10 mM MgCl2 and 5 mM ATP at room temperature for one hour. Typical reaction solutions (50 μL final reaction volume) contained 2% DMSO (±inhibitor), 4 mM MgCl2, 1 mM DTT, 150 μM ATP (ATP Km=67.4 μM), 0.005% Tween-20, 3 μM FL-Peptide-18, and 0.36 nM (catalytically competent active site) phosphorylated wild-type full length CDK2/Cyclin E1 enzyme complex in 25 mM HEPES buffer at pH 7.15. The assay was initiated with the addition of ATP, following a fifteen minutes pre-incubation of enzyme and inhibitor at room temperature in the reaction mixture. The reaction was stopped after 45 minutes at room temperature by the addition of 50 μL of 80 mM EDTA.
Measurement: Ki = 0.22 nM (pChEMBL 9.65999984741211)
Descriptors: MW 443.43, ALogP 3.59, HBA 6, HBD 3, PSA 122.14, QED 0.6
Compound (SMILES): CCN1CCN(c2ccc(Nc3ncc(F)c(-c4cc5nccc(C6CCCC6)c5s4)n3)nc2)CC1
InChIKey: MKQNODLXALTYDJ-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 4/cyclin D1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P11802
Assay: Enzymatic Activity Assay: The inhibitory activity of compounds was evaluated in vitro using TR-FRET assay with white 384-well low volume microplate (Greiner Bio-One). CDK4/Cyclin D1 catalyzed phosphorylation of peptide in the presence and absence of compounds was measured. IC50 determination. Recombinant protein complex CDK4/Cyclin D1, expressed from insect cell, was purchased from ProQinase. Testing compounds were dissolved in DMSO at 0.1 mM and tested in 9-dose IC50 mode. The reaction mixture was prepared by mixing CDK4/CyclinD1 (1 nM final), ULight-4E-BP1 (100 nM final, Perkinelmer, TRF0128-D), and ATP (2 mM final) in assay buffer (20 mM of HEPES pH 7.4, 1 mM of EGTA, 0.05% BSA, 0.005% Tween 20, and 1 mM TCEP). The compound of interest in DMSO was added to each well in 3-fold serial dilution by dispenser (TECAN D300E). After 20 minutes preincubation at room temperature, MgCl2(10 mM final) was added to initiate the reaction. Following a 60 minutes incubation at 37° C., the reaction was stopped by addition of 2 μL of quenching buffer consisting of Lance detection buffer (Perkinelmer CR97-100C), 2 nM LANCE Ultra Europium-anti-P-4E-BP1 (Perkinelmer, TRF0216-D), 10 mM EDTA, and incubate at room temperature for additional 60 minutes in dark. The reaction signal was measured by Envision multimode plate reader (PerkinElmer, 2102-0010).
Measurement: IC50 = 110 nM (pChEMBL 6.960000038146973)
Descriptors: MW 503.65, ALogP 5.83, HBA 8, HBD 1, PSA 70.07, QED 0.35
Compound (SMILES): CNc1cc2n(c(=O)c1)CC1CNC[C@@H]2C1
InChIKey: PQACGZHZKXPWQM-GKAPJAKFSA-N
Target: Neuronal acetylcholine receptor; alpha3/beta4 (PROTEIN COMPLEX), Homo sapiens
UniProt: P30926
Assay: Binding to Nicotinic Receptor Subtypes: The binding of a group of compounds mentioned above were tested for their affinity at different nAChR subtypes, specifically the α4β2, the α3β4 and α7. The protocol for these tests is set out below, and the results are provided at Table 1 below. Binding to Heterologously Expressed_α4β2 and α3β4 Human SubtypesHEK 293 cells were grown in Dulbecco's modified Eagle medium supplemented with 10% fetal bovine serum, 1% L-Glutamine, 100 units/ml penicillin G, and 100 μg/streptomycin in a humidified atmosphere containing 10% CO2. The cDNAs encoding α3 and β4 or α4 and β2 (were transfected into the HEK 293 cells at 30% confluency). The cell transfections were carried out in 100 mm Petri dishes using 30 μL of JetPEI (Polypus, France) (1 mg/ml, pH 7.2) and 3 μg of each cDNA. After 24 h transfection, the cells were collected, washed with PBS by centrifugation, and used for binding analysis.[3H]-epibatidine saturation binding experiments to HEK transfected α3β4 or α4β2 receptors were performed by means of overnight incubation at 4° C. at concentrations ranging from 0.005 to 1 nM in a buffer containing 50 mM Tris-HCl, pH 7, 150 mM NaCl, 5 mM KCl, 1 mM MgCl2, 2.5 mM CaCl2and 2 mg/ml BSA, in the presence (aspecific binding) or absence (total binding) of 100 nM cold epibatidine. Specific ligand binding was defined as total binding minus the binding in the presence of 100 nM cold epibatidine.
Measurement: Ki = 27500 nM (pChEMBL 4.559999942779541)
Descriptors: MW 219.29, ALogP 0.6, HBA 4, HBD 2, PSA 46.06, QED 0.73
Compound (SMILES): Cc1c(-c2nc(Nc3ccc(C4CN(C)C4)cn3)ncc2F)sc2c1nc(C)n2C(C)C
InChIKey: MCGYAQRNWYNCMH-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 4/cyclin D1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P11802
Assay: Enzymatic Activity Assay: The inhibitory activity of compounds was evaluated in vitro using TR-FRET assay with white 384-well low volume microplate (Greiner Bio-One). CDK4/Cyclin D1 catalyzed phosphorylation of peptide in the presence and absence of compounds was measured. IC50 determination. Recombinant protein complex CDK4/Cyclin D1, expressed from insect cell, was purchased from ProQinase. Testing compounds were dissolved in DMSO at 0.1 mM and tested in 9-dose IC50 mode. The reaction mixture was prepared by mixing CDK4/CyclinD1 (1 nM final), ULight-4E-BP1 (100 nM final, Perkinelmer, TRF0128-D), and ATP (2 mM final) in assay buffer (20 mM of HEPES pH 7.4, 1 mM of EGTA, 0.05% BSA, 0.005% Tween 20, and 1 mM TCEP). The compound of interest in DMSO was added to each well in 3-fold serial dilution by dispenser (TECAN D300E). After 20 minutes preincubation at room temperature, MgCl2(10 mM final) was added to initiate the reaction. Following a 60 minutes incubation at 37° C., the reaction was stopped by addition of 2 μL of quenching buffer consisting of Lance detection buffer (Perkinelmer CR97-100C), 2 nM LANCE Ultra Europium-anti-P-4E-BP1 (Perkinelmer, TRF0216-D), 10 mM EDTA, and incubate at room temperature for additional 60 minutes in dark. The reaction signal was measured by Envision multimode plate reader (PerkinElmer, 2102-0010).
Measurement: IC50 < 20 nM (pChEMBL 7.698999881744385)
Descriptors: MW 451.58, ALogP 5.06, HBA 8, HBD 1, PSA 71.76, QED 0.46
Compound (SMILES): CNS(=O)(=O)N1CCC(Nc2ncc3cc(C)c(=O)n(C4CCCC4)c3n2)CC1
InChIKey: YNZJEXZWSZMQGW-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 2/cyclin E1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24941
Assay: CDK2/Cyclin E1 Mobility Shift Assay: The purpose of the CDK2/Cyclin E1 assay is to evaluate the inhibition (% inhibition, Kiapp and Ki values) of small molecule inhibitors by using a fluorescence-based microfluidic mobility shift assay. CDK2/Cyclin E1 catalyzes the production of ADP from ATP that accompanies the phosphoryl transfer to the substrate peptide FL-Peptide-18 (5-FAM-QSPKKG-CONH2) (SEQ ID NO:1). (CPC Scientific, Sunnyvale, Calif.). The mobility shift assay electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product) following the kinase reaction. Both substrate and product are measured and the ratio of these values is used to generate % conversion of substrate to product by the LabChip EZ Reader. Wild-type full length CDK2/wild-type full length Cyclin E1 enzyme complex was produced in-house (baculoviral expression, LJIC-2080/LJIC-2103) and phosphorylated by CDK7/Cyclin H1/Mat1 enzyme complex with CDK2:CDK7 ratio of 50:1 (concentration mg/mL) in the presence of 10 mM MgCl2 and 5 mM ATP at room temperature for one hour. Typical reaction solutions (50 μL final reaction volume) contained 2% DMSO (± inhibitor), 4 mM MgCl2, 1 mM DTT, 150 μM ATP (ATP Km=67.4 μM), 0.005% Tween-20, 3 μM FL-Peptide-18, and 0.36 nM (catalytically competent active site) phosphorylated wild-type full length CDK2/Cyclin E1 enzyme complex in 25 mM HEPES buffer at pH 7.15. The assay was initiated with the addition of ATP, following a fifteen minutes pre-incubation of enzyme and inhibitor at room temperature in the reaction mixture. The reaction was stopped after 45 minutes at room temperature by the addition of 50 μL of 80 mM EDTA, pH 7.5. The Ki value was determined from the fit of the data to the Morrison tight-binding competitive inhibition equation with the enzyme concentration as a variable.
Measurement: Ki = 0.78 nM (pChEMBL 9.109999656677246)
Descriptors: MW 420.54, ALogP 1.56, HBA 7, HBD 2, PSA 109.22, QED 0.76
Compound (SMILES): Cc1cc(S(=O)(=O)N[C@H](c2n[nH]c(=O)o2)[C@H](C)c2c(F)ccc(C)c2C)c(C(N)=O)cc1Cl
InChIKey: RUCYNEILMKNPMV-XIKOKIGWSA-N
Target: Ribonucleotide reductase (PROTEIN COMPLEX), Homo sapiens
UniProt: Q7LG56
Assay: Human RNR Inhibition Effect: The inhibitory activity against the ribonucleotide reduction reaction (hereinafter referred to as RNR reaction) of the test compound was determined by measuring the formation of deoxycytidine diphosphate (hereinafter referred to as dCDP) from cytidine diphosphate (hereinafter referred to as CDP) by the following method.Human M1 subunit and human M2 subunit (mutant lacking amino terminal 59 amino acids), which are fused a histidine tag at the amino terminus, are overexpressed in Escherichia coli and are solubilized after collection, and histidine tagged human M1 and M2 proteins were purified on a nickel chelate column.For measuring the inhibitory activity of the test compound against the RNR reaction, the method described in the document [CANCER RESEARCH 64, 1-6, 2004] was referred to.
Measurement: IC50 = 100 nM (pChEMBL 7)
Descriptors: MW 496.95, ALogP 3, HBA 6, HBD 3, PSA 148.15, QED 0.46
Compound (SMILES): COc1cccc(OC)c1-c1ccnc2[nH]c(C3=CCNCC3)cc12
InChIKey: XOEVDAPBJZCOGR-UHFFFAOYSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: LANCE ULight TR-FRET Kinase Assay: CDK9 enzyme activities were measured using LANCE ULight TR-FRET kinase assay reagents (PerkinElmer, Waltham, Mass.). Compounds were directly added in 100% DMSO to white low volume assay plates (Perkin Elmer Proxiplate 6008289) using a Labcyte Echo acoustic dispenser. Assay reagents in serine/threonine kinase assay buffer containing 20 mM HEPES, 10 mM MgCl2, 100 mM Na3VO4, and 0.0075% Triton X-100. were added for final reaction mixture concentrations of 1000 μM ATP, 100 nM U-light MBP peptide (Perkin Elmer TRF0109M) and reaction initiated with 4 nM CDK9/Cyclin T1 (Carna Biosciences 04-110). The kinase reaction was carried out for 30 minutes before addition of stopping buffer to a final of 20 mM EDTA and 0.5 nM of LANCE Ultra Europium anti-phospho-MBP antibody (PerkinElmer TRF0201M) in LANCE detection buffer (PerkinElmer CR97-100). The reaction was equilibrated for 1 hour and the signal read in the Perkin Elmer Envision in TR-FRET mode (excitation at 320 nm and emission at 615/665 nm).
Measurement: IC50 = 210 nM (pChEMBL 6.679999828338623)
Descriptors: MW 335.41, ALogP 3.62, HBA 4, HBD 2, PSA 59.17, QED 0.76
Compound (SMILES): COc1ccc(CC(=O)Nc2cc([C@H]3CC[C@@H](OC(=O)NC4(C)CCOC4)C3)[nH]n2)cc1
InChIKey: GQJJOIYDBRPPCC-LRUZPBGCSA-N
Target: Cyclin-dependent kinase 2/cyclin E1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24941
Assay: Biochemical Assay: The purpose of CDK2/Cyclin E1 assay is to evaluate the inhibition (% inhibition, Kiapp and Ki values) of small molecule inhibitors by using a fluorescence-based microfluidic mobility shift assay. CDK2/Cyclin E1 full length catalyzes the production of ADP from ATP that accompanies the phosphoryl transfer to the substrate peptide FL-Peptide-18 (5-FAM-QSPKKG-CONH2, CPC Scientific, Sunnyvale, Calif.) (SEQ ID NO:1). The mobility shift assay electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product) following the kinase reaction. Both substrate and product are measured and the ratio of these values is used to generate % conversion of substrate to product by the LabChip EZ Reader. Wild-type CDK2/wild-type full length Cyclin E1 enzyme complex was produced in-house (baculoviral expression, LJIC-2080/LJIC-2103) and phosphorylated by CDK7/Cyclin H1/Matl enzyme complex with CDK2:CDK7 ratio of 50:1 (concentration mg/mL) in the presence of 10 mM MgCl2 and 5 mM ATP at room temperature for one hour. Typical reaction solutions (50 μL final reaction volume) contained 2% DMSO (±inhibitor), 4 mM MgCl2, 1 mM DTT, 150 μM ATP (ATP Km=67.4 μM), 0.005% Tween-20, 3 μM FL-Peptide-18, and 0.36 nM (catalytically competent active site) phosphorylated wild-type full length CDK2/Cyclin E1 enzyme complex in 25 mM HEPES buffer at pH 7.15. The assay was initiated with the addition of ATP, following a fifteen minutes pre-incubation of enzyme and inhibitor at room temperature in the reaction mixture. The reaction was stopped after 45 minutes at room temperature by the addition of 50 μL of 80 mM EDTA.
Measurement: Ki = 0.32 nM (pChEMBL 9.489999771118164)
Descriptors: MW 442.52, ALogP 3.14, HBA 6, HBD 3, PSA 114.57, QED 0.61
Compound (SMILES): COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(C(=O)Nc4cnn(CC(=O)O)c4)CC3)cc12
InChIKey: XOJVFCFJRDSTIM-UHFFFAOYSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: LANCE ULight TR-FRET Kinase Assay: CDK9 enzyme activities were measured using LANCE ULight TR-FRET kinase assay reagents (PerkinElmer, Waltham, Mass.). Compounds were directly added in 100% DMSO to white low volume assay plates (Perkin Elmer Proxiplate 6008289) using a Labcyte Echo acoustic dispenser. Assay reagents in serine/threonine kinase assay buffer containing 20 mM HEPES, 10 mM MgCl2, 100 mM Na3VO4, and 0.0075% Triton X-100. were added for final reaction mixture concentrations of 1000 μM ATP, 100 nM U-light MBP peptide (Perkin Elmer TRF0109M) and reaction initiated with 4 nM CDK9/Cyclin T1 (Carna Biosciences 04-110). The kinase reaction was carried out for 30 minutes before addition of stopping buffer to a final of 20 mM EDTA and 0.5 nM of LANCE Ultra Europium anti-phospho-MBP antibody (PerkinElmer TRF0201M) in LANCE detection buffer (PerkinElmer CR97-100). The reaction was equilibrated for 1 hour and the signal read in the Perkin Elmer Envision in TR-FRET mode (excitation at 320 nm and emission at 615/665 nm).
Measurement: IC50 = 59 nM (pChEMBL 7.230000019073486)
Descriptors: MW 490.5, ALogP 3.98, HBA 6, HBD 3, PSA 125.37, QED 0.38
Compound (SMILES): C=CC(=O)Nc1ccc(-c2cccc(C(C(=O)Nc3cc(C4CC4)[nH]n3)C(C)C)c2)cc1F
InChIKey: QRHXYRZCHFIWGD-UHFFFAOYSA-N
Target: CDK7/Cyclin H/MNAT1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P51946
Assay: Biochemical Assay: The ability of compounds to inhibit CDK7 kinase activity was tested in a TR-FRET assay using 5 nM of CDK7/CycH/MNAT1 obtained from Invitrogen, USA. Test compounds were pre-incubated with the kinase at room temperature for 60 min. After the incubation, substrate mix [100 nM Ultra-light MBP (Perkin Elmer, USA) and 1 mM ATP (Sigma)] was added. The above reaction was stopped by the addition of 40 mM EDTA after 60 minutes of kinase reaction. 1 nM Eu-labelled antiphospho-MBP antibody [Perkin Elmer, USA] was added, mixed well and the fluorescence emission at 615 nm and 665 nm [excitation at 340 nm] was measured. The final DMSO concentration in the assay was 1%. For IC50 determination, appropriate concentrations were made by ⅓rd serial dilutions of 10 mM DMSO stock solution of test compound. All the fluorescence measurements were made in a Victor 3 Multilabel Counter [Perkin Elmer, USA]. The IC50 was determined by fitting the dose response data to sigmoidal curve fitting equation using GraphPad Prism software V5. To identify compounds that inhibit CDK7 irreversibly, time depended inhibition studies were carried by pre-incubating compound with the enzyme at three time points (20, 60 and 180 min) and carrying out assay as described above.
Measurement: IC50 = 62.5 nM (pChEMBL 7.199999809265137)
Descriptors: MW 446.53, ALogP 5.6, HBA 3, HBD 3, PSA 86.88, QED 0.39
Compound (SMILES): CNC(=O)c1nc2c(F)cc(-c3nc(N[C@@H]4CCOC[C@H]4O)ncc3Cl)cc2n1C(C)C
InChIKey: FIQBYSRAADOZQW-GDBMZVCRSA-N
Target: Cyclin-dependent kinase 4/cyclin D1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P11802
Assay: Biological Assay: CDK4/Cyclin D1: The purpose CDK4/Cyclin D1 assay is to evaluate the inhibition (% inhibition, Kiapp and Ki values) in the presence of small molecule inhibitors by using a fluorescence based microfluidic mobility shift assay. CDK4/Cyclin D1 catalyzes the production of ADP from ATP that accompanies the phosphoryl transfer to the substrate peptide 5-FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (SEQ ID NO:1). The mobility shift assay electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product) following the kinase reaction. Both substrate and product are measured and the ratio of these values is used to generate % Conversion of substrate to product by the LabChip EZ Reader. Typical reaction solutions contained 2% DMSO (±inhibitor), 10 mM MgCl2, 1 mM DTT, 3.5 mM ATP, 0.005% TW-20, 3 μM 5-FAM-Dyrktide, 3 nM (active sites) activated CDK4/Cyclin D1 in 40 mM HEPES buffer at pH 7.5.
Measurement: Ki = 11.1 nM (pChEMBL 7.960000038146973)
Descriptors: MW 462.91, ALogP 2.79, HBA 8, HBD 3, PSA 114.19, QED 0.53
Compound (SMILES): CCN1CCN(C(=O)c2ccc(Nc3ncc(F)c(-c4cc(F)c5nc6n(c5c4)C(C)(C)CC6)n3)nc2)CC1
InChIKey: OABDCOIDBQVRDT-UHFFFAOYSA-N
Target: CDK4/Cyclin D3 (PROTEIN COMPLEX), Homo sapiens
UniProt: P11802
Assay: Inhibition Assay: In vitro inhibition of CDK (CDK1, CDK4, CDK6) activity by compounds of the present invention was tested by the following method.1. Preparation of kinase reaction buffer I: 5× Reaction Buffer A (Promega; V307A-C) provided in the kit was diluted with a mixture of Milli Q H2O and 0.1M DTT (dithiothreitol) to 4× kinase buffer; then Milli Q H2O was added in a proper proportion, to finally formulate into 1× kinase buffer.Preparation of kinase reaction buffer II: 0.5% DMSO (dimethyl sulfoxide) was added into 1× kinase reaction buffer and uniformly mixed to obtain the title buffer.2. Preparation of kinase solution: 100 ng/μl kinase stock solution was formulated with 1× kinase reaction buffer into kinase solution with the desired concentration for each reaction system.3. Preparation of solution of test compound and LY2835219 as a control:(1) Preparation of Solution of LY2835219 as a Controla. 1 μl of 10 mM standard stock solution was added respectively into 9 μl of kinase reaction buffer I and uniformly mixed; then 90 μl of kinase reaction buffer I was added and uniformly mixed; and then 100 μl of kinase reaction buffer I was added and uniformly mixed, to achieve a final concentration of 50 μM.b. 40 μl of kinase reaction buffer II was added into Well B2-B10 of a 96-well plate; and 50 μl of above-mentioned solution was added into Well B1;c. 10 μl of solution was taken from Well B1, added into Well B2 and uniformly mixed, then 10 μl of dilution was taken from Well B2 and added into Well B3, the serial dilution was continued up to B9, to obtain 5-fold serial dilutions of the reference solution.
Measurement: IC50 = 49000 nM (pChEMBL 4.309999942779541)
Descriptors: MW 532.6, ALogP 4.37, HBA 8, HBD 1, PSA 92.07, QED 0.41
Compound (SMILES): CS(=O)(=O)N1CC=C(c2cc3c(-c4cc(NCC5CCOCC5)c(F)cc4F)ccnc3[nH]2)CC1
InChIKey: SNWBHJJMZYXGNS-UHFFFAOYSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: LANCE ULight TR-FRET Kinase Assay: CDK9 enzyme activities were measured using LANCE ULight TR-FRET kinase assay reagents (PerkinElmer, Waltham, Mass.). Compounds were directly added in 100% DMSO to white low volume assay plates (Perkin Elmer Proxiplate 6008289) using a Labcyte Echo acoustic dispenser. Assay reagents in serine/threonine kinase assay buffer containing 20 mM HEPES, 10 mM MgCl2, 100 mM Na3VO4, and 0.0075% Triton X-100. were added for final reaction mixture concentrations of 1000 μM ATP, 100 nM U-light MBP peptide (Perkin Elmer TRF0109M) and reaction initiated with 4 nM CDK9/Cyclin T1 (Carna Biosciences 04-110). The kinase reaction was carried out for 30 minutes before addition of stopping buffer to a final of 20 mM EDTA and 0.5 nM of LANCE Ultra Europium anti-phospho-MBP antibody (PerkinElmer TRF0201M) in LANCE detection buffer (PerkinElmer CR97-100). The reaction was equilibrated for 1 hour and the signal read in the Perkin Elmer Envision in TR-FRET mode (excitation at 320 nm and emission at 615/665 nm).
Measurement: IC50 = 160 nM (pChEMBL 6.800000190734863)
Descriptors: MW 502.59, ALogP 4.4, HBA 5, HBD 2, PSA 87.32, QED 0.52
Compound (SMILES): CC(C)(O)CC1NCCC1C(=O)N[C@@H](CCN1CC(OCCc2ccc3c(n2)NCCC3)C1)C(=O)O
InChIKey: MEIHPOHAALPWQY-ORFBVSJDSA-N
Target: Integrin alpha-V/beta-6 (PROTEIN COMPLEX), Homo sapiens
UniProt: P18564
Assay: Binding Assay: Microplates were coated with recombinant human integrin αvβ6 (2 ug/ml) in PBS (100 ul/well 25° C., overnight). The coating solution was removed, washed with wash buffer (0.05% Tween 20; 0.5 mM MnCl2; in 1×TBS). Plate was blocked with 200 ul/well of Block Buffer (1% BSA; 5% sucrose; 0.5 mM MnCl2; in 1×TBS) at 37° C. for 2 h. Dilutions of testing compounds and recombinant TGFβ1 LAP (0.67 ug/ml) in binding buffer (0.05% BSA; 2.5% sucrose; 0.5 mM MnCl2; in 1×TBS) were added. The plate was incubated for 2 hours at 25° C., washed, and incubated for 1 hour with Biotin-Anti-hLAP. Bound antibody was detected by peroxidase-conjugated streptavidin. The IC50 values for testing compounds were calculated by a four-parameter logistic regression.
Measurement: IC50 = 625 nM (pChEMBL 6.199999809265137)
Descriptors: MW 503.64, ALogP 0.78, HBA 8, HBD 5, PSA 136.05, QED 0.28
Compound (SMILES): CCN(CC)Cc1ccc(-n2cc(-c3nc(NC4CCN(S(C)(=O)=O)CC4)ncc3C(F)(F)F)nc2C)c(F)c1
InChIKey: YOUJOZJVKJVKRT-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 2/cyclin E1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24941
Assay: HTRF Enzyme Activity Assay: CDK2/Cyclin E1 enzyme activity assays utilize full-length human CDK2 co-expressed as N-terminal GST-tagged protein with FLAG-Cyclin E1 in a baculovirus expression system (Carna Product Number 04-165). Assays were conducted in white 384-well polystyrene plates in a final reaction volume of 8 μL. CDK2/Cyclin E1 (0.25 nM) was incubated with the compounds of the Examples (40 nL serially diluted in DMSO) in the presence of ATP (50 μM or 1 mM) and 50 nM ULight-labeled eIF4E-binding protein 1 (THR37/46) peptide (PerkinElmer) in assay buffer (containing 50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.05 mg/mL BSA, and 0.01% Tween 20) for 60 minutes at room temperature. The reactions were stopped by the addition of EDTA and Europium-labeled anti-phospho-4E-BP1 antibody (PerkinElmer), for a final concentration of 15 mM and 1.5 nM, respectively. HTRF signals were read after 1 hour at room temperature on a PHERAstar FS plate reader (BMG Labtech). Data was analyzed with IDBS XLFit and GraphPad Prism 5.0 software using a three or four parameter dose response curve to determine IC50 for each compound.
Measurement: IC50 < 50 nM (pChEMBL 7.301000118255615)
Descriptors: MW 583.66, ALogP 4.47, HBA 8, HBD 1, PSA 96.25, QED 0.37
Compound (SMILES): C=CC(=O)NC1CCC(C(=O)Nc2cccc(Nc3nc(OC4CCN(C)CC4)nc4c(C(C)C)cnn34)c2)CC1
InChIKey: XBTMRUWGUMUPAK-UHFFFAOYSA-N
Target: CDK7/Cyclin H/MNAT1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P51946
Assay: Biochemical Assay for CDK7: The ability of compounds to inhibit CDK7 kinase activity was tested in a TR-FRET assay using 5 nM of CDK7/CycH/MNAT1 obtained from Invitrogen, USA. Test compounds were pre-incubated with the kinase at room temperature for 60 min. After incubation, substrate mix [100 nM Ultra-light MBP (Perkin Elmer, USA) and 1 mM ATP (Sigma)] was added. The above reaction was stopped by the addition of 40 mM EDTA after 60 minutes of kinase reaction. 1 nM Eu-labelled antiphospho-MBP antibody [Perkin Elmer, USA] was added, mixed well and the fluorescence emission at 615 nm and 665 nm [excitation at 340 nm] was measured. The final DMSO concentration in the assay was 1%. For IC50 determination, appropriate concentrations were made by ⅓rd serial dilutions of 10 mM DMSO stock solution of test compound. All the fluorescence measurements were made in a Victor 3 Multilabel Counter [Perkin Elmer, USA]. The IC50 was determined by fitting the dose response data to sigmoidal curve fitting equation using GraphPad Prism software V5. To identify compounds that inhibit CDK7 irreversibly, time depended inhibition studies were carried by pre-incubating compound with the enzyme at three time points (20, 60 and 180 min) and carrying out assay as described above.
Measurement: IC50 > 1000 nM (pChEMBL 6)
Descriptors: MW 560.7, ALogP 4.26, HBA 9, HBD 3, PSA 125.78, QED 0.33
Compound (SMILES): COC/C=C/C(=O)N1CCC(C(=O)Nc2cccc(CNc3nc(NC4CCOCC4)nc4c(C(C)C)cnn34)c2)C1
InChIKey: SDHIXASQHYFOME-VMPITWQZSA-N
Target: CDK7/Cyclin H/MNAT1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P51946
Assay: Biochemical Assay for CDK7: The ability of compounds to inhibit CDK7 kinase activity was tested in a TR-FRET assay using 5 nM of CDK7/CycH/MNAT1 obtained from Invitrogen, USA. Test compounds were pre-incubated with the kinase at room temperature for 60 min. After incubation, substrate mix [100 nM Ultra-light MBP (Perkin Elmer, USA) and 1 mM ATP (Sigma)] was added. The above reaction was stopped by the addition of 40 mM EDTA after 60 minutes of kinase reaction. 1 nM Eu-labelled antiphospho-MBP antibody [Perkin Elmer, USA] was added, mixed well and the fluorescence emission at 615 nm and 665 nm [excitation at 340 nm] was measured. The final DMSO concentration in the assay was 1%. For IC50 determination, appropriate concentrations were made by ⅓rd serial dilutions of 10 mM DMSO stock solution of test compound. All the fluorescence measurements were made in a Victor 3 Multilabel Counter [Perkin Elmer, USA]. The IC50 was determined by fitting the dose response data to sigmoidal curve fitting equation using GraphPad Prism software V5. To identify compounds that inhibit CDK7 irreversibly, time depended inhibition studies were carried by pre-incubating compound with the enzyme at three time points (20, 60 and 180 min) and carrying out assay as described above.
Measurement: IC50 = 650 nM (pChEMBL 6.190000057220459)
Descriptors: MW 576.7, ALogP 3.44, HBA 10, HBD 3, PSA 135.01, QED 0.29
Compound (SMILES): COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(CC(=O)NC#N)CC3)cc12
InChIKey: BCGQYCBBSGSWAW-UHFFFAOYSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: LANCE ULight TR-FRET Kinase Assay: CDK9 enzyme activities were measured using LANCE ULight TR-FRET kinase assay reagents (PerkinElmer, Waltham, Mass.). Compounds were directly added in 100% DMSO to white low volume assay plates (Perkin Elmer Proxiplate 6008289) using a Labcyte Echo acoustic dispenser. Assay reagents in serine/threonine kinase assay buffer containing 20 mM HEPES, 10 mM MgCl2, 100 mM Na3VO4, and 0.0075% Triton X-100. were added for final reaction mixture concentrations of 1000 μM ATP, 100 nM U-light MBP peptide (Perkin Elmer TRF0109M) and reaction initiated with 4 nM CDK9/Cyclin T1 (Carna Biosciences 04-110). The kinase reaction was carried out for 30 minutes before addition of stopping buffer to a final of 20 mM EDTA and 0.5 nM of LANCE Ultra Europium anti-phospho-MBP antibody (PerkinElmer TRF0201M) in LANCE detection buffer (PerkinElmer CR97-100). The reaction was equilibrated for 1 hour and the signal read in the Perkin Elmer Envision in TR-FRET mode (excitation at 320 nm and emission at 615/665 nm).
Measurement: IC50 = 71 nM (pChEMBL 7.150000095367432)
Descriptors: MW 407.45, ALogP 3.15, HBA 5, HBD 2, PSA 94.04, QED 0.5
Compound (SMILES): COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CC4CN(S(C)(=O)=O)CC4C3)c(C#N)c12
InChIKey: BZBOETDXDXTOGW-UHFFFAOYSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: LANCE ULight TR-FRET Kinase Assay: CDK9 enzyme activities were measured using LANCE ULight TR-FRET kinase assay reagents (PerkinElmer, Waltham, Mass.). Compounds were directly added in 100% DMSO to white low volume assay plates (Perkin Elmer Proxiplate 6008289) using a Labcyte Echo acoustic dispenser. Assay reagents in serine/threonine kinase assay buffer containing 20 mM HEPES, 10 mM MgCl2, 100 mM Na3VO4, and 0.0075% Triton X-100. were added for final reaction mixture concentrations of 1000 μM ATP, 100 nM U-light MBP peptide (Perkin Elmer TRF0109M) and reaction initiated with 4 nM CDK9/Cyclin T1 (Carna Biosciences 04-110). The kinase reaction was carried out for 30 minutes before addition of stopping buffer to a final of 20 mM EDTA and 0.5 nM of LANCE Ultra Europium anti-phospho-MBP antibody (PerkinElmer TRF0201M) in LANCE detection buffer (PerkinElmer CR97-100). The reaction was equilibrated for 1 hour and the signal read in the Perkin Elmer Envision in TR-FRET mode (excitation at 320 nm and emission at 615/665 nm).
Measurement: IC50 = 2300 nM (pChEMBL 5.639999866485596)
Descriptors: MW 470.5, ALogP 3.68, HBA 5, HBD 1, PSA 99.08, QED 0.63
Compound (SMILES): COc1ccc(CC(=O)Nc2cc([C@@H]3CC[C@H](OC(=O)N[C@H]4CC[C@@](C)(O)CC4)C3)[nH]n2)cc1
InChIKey: QBXUCZWIDBSQSN-QCKQGSCRSA-N
Target: Cyclin-dependent kinase 2/cyclin E1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24941
Assay: Biochemical Assay: The purpose of CDK2/Cyclin E1 assay is to evaluate the inhibition (% inhibition, Kiapp and Ki values) of small molecule inhibitors by using a fluorescence-based microfluidic mobility shift assay. CDK2/Cyclin E1 full length catalyzes the production of ADP from ATP that accompanies the phosphoryl transfer to the substrate peptide FL-Peptide-18 (5-FAM-QSPKKG-CONH2, CPC Scientific, Sunnyvale, Calif.) (SEQ ID NO:1). The mobility shift assay electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product) following the kinase reaction. Both substrate and product are measured and the ratio of these values is used to generate % conversion of substrate to product by the LabChip EZ Reader. Wild-type CDK2/wild-type full length Cyclin E1 enzyme complex was produced in-house (baculoviral expression, LJIC-2080/LJIC-2103) and phosphorylated by CDK7/Cyclin H1/Matl enzyme complex with CDK2:CDK7 ratio of 50:1 (concentration mg/mL) in the presence of 10 mM MgCl2 and 5 mM ATP at room temperature for one hour. Typical reaction solutions (50 μL final reaction volume) contained 2% DMSO (±inhibitor), 4 mM MgCl2, 1 mM DTT, 150 μM ATP (ATP Km=67.4 μM), 0.005% Tween-20, 3 μM FL-Peptide-18, and 0.36 nM (catalytically competent active site) phosphorylated wild-type full length CDK2/Cyclin E1 enzyme complex in 25 mM HEPES buffer at pH 7.15. The assay was initiated with the addition of ATP, following a fifteen minutes pre-incubation of enzyme and inhibitor at room temperature in the reaction mixture. The reaction was stopped after 45 minutes at room temperature by the addition of 50 μL of 80 mM EDTA.
Measurement: Ki = 0.37 nM (pChEMBL 9.430000305175781)
Descriptors: MW 470.57, ALogP 3.66, HBA 6, HBD 4, PSA 125.57, QED 0.49
Compound (SMILES): C=CC(=O)Nc1ccc(C(=O)Nc2cccc(Nc3n[nH]c4c3CN(C(=O)NC(C)CN(C)C)C4(C)C)c2)cc1
InChIKey: WMCXSDYNICXFAU-UHFFFAOYSA-N
Target: CDK7/Cyclin H/MNAT1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P50613
Assay: Inhibition of Kinase Activity: Compounds of the invention were assayed for activity against a variety of different kinases.
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 544.66, ALogP 4.24, HBA 6, HBD 5, PSA 134.49, QED 0.26
Compound (SMILES): OCC1(CO)CN(Cc2ccc(-c3ccc(-c4nc5nc(O[C@@H]6CO[C@H]7[C@@H]6OC[C@H]7O)[nH]c5cc4Cl)cc3)cc2)C1
InChIKey: RMPLNWAYEWJALN-UDCKCYQBSA-N
Target: AMP-activated protein kinase (AMPK) alpha-1/beta-1/gamma-1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q9Y478
Assay: In Vitro pAMPK1 Kinase Activation Assay: Compound effect on AMPK enzyme activation was determined in a cell-free format with a 12-point concentration curve. The ADP-Glo detection system was used to determine phosphorylation of a SAMS peptide substrate. Recombinant AMPK α1/β1/γ1 complex was pre-activated by phosphorylation with CAMKK2 followed by incubated with compound for 15 minutes prior to the SAMS phosphorylation reaction. Activity curves and EC50 values were fitted by interpolation to an ATP:ADP standard curve as indicated by the ADP-Glo manufacturer using Prism software.
Measurement: EC50 = 0.81 nM (pChEMBL 9.09000015258789)
Descriptors: MW 579.05, ALogP 2.64, HBA 9, HBD 4, PSA 133.19, QED 0.25
Compound (SMILES): C=CC(=O)Nc1ccc(-c2cccc(C(C(=O)Nc3cc(C4CC4)[nH]n3)C(C)C)c2)cc1F
InChIKey: QRHXYRZCHFIWGD-UHFFFAOYSA-N
Target: CDK7/Cyclin H/MNAT1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P50613
Assay: Biochemical Assay: The ability of compounds to inhibit CDK7 kinase activity was tested in a TR-FRET assay using 5 nM of CDK7/CycH/MNAT1 obtained from Invitrogen, USA. Test compounds were pre-incubated with the kinase at room temperature for 60 min. After the incubation, substrate mix [100 nM Ultra-light MBP (Perkin Elmer, USA) and 1 mM ATP (Sigma)] was added. The above reaction was stopped by the addition of 40 mM EDTA after 60 minutes of kinase reaction. 1 nM Eu-labelled antiphospho-MBP antibody [Perkin Elmer, USA] was added, mixed well and the fluorescence emission at 615 nm and 665 nm [excitation at 340 nm] was measured. The final DMSO concentration in the assay was 1%. For IC50 determination, appropriate concentrations were made by ⅓rd serial dilutions of 10 mM DMSO stock solution of test compound. All the fluorescence measurements were made in a Victor 3 Multilabel Counter [Perkin Elmer, USA]. The IC50 was determined by fitting the dose response data to sigmoidal curve fitting equation using GraphPad Prism software V5. To identify compounds that inhibit CDK7 irreversibly, time depended inhibition studies were carried by pre-incubating compound with the enzyme at three time points (20, 60 and 180 min) and carrying out assay as described above.
Measurement: IC50 = 62.5 nM (pChEMBL 7.199999809265137)
Descriptors: MW 446.53, ALogP 5.6, HBA 3, HBD 3, PSA 86.88, QED 0.39
Compound (SMILES): C=CC(=O)NC1CCC(C(=O)Nc2cccc(Nc3nc(OC4CCN(C)CC4)nc4c(C(C)C)cnn34)c2)CC1
InChIKey: XBTMRUWGUMUPAK-UHFFFAOYSA-N
Target: CDK7/Cyclin H/MNAT1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P50613
Assay: Biochemical Assay for CDK7: The ability of compounds to inhibit CDK7 kinase activity was tested in a TR-FRET assay using 5 nM of CDK7/CycH/MNAT1 obtained from Invitrogen, USA. Test compounds were pre-incubated with the kinase at room temperature for 60 min. After incubation, substrate mix [100 nM Ultra-light MBP (Perkin Elmer, USA) and 1 mM ATP (Sigma)] was added. The above reaction was stopped by the addition of 40 mM EDTA after 60 minutes of kinase reaction. 1 nM Eu-labelled antiphospho-MBP antibody [Perkin Elmer, USA] was added, mixed well and the fluorescence emission at 615 nm and 665 nm [excitation at 340 nm] was measured. The final DMSO concentration in the assay was 1%. For IC50 determination, appropriate concentrations were made by ⅓rd serial dilutions of 10 mM DMSO stock solution of test compound. All the fluorescence measurements were made in a Victor 3 Multilabel Counter [Perkin Elmer, USA]. The IC50 was determined by fitting the dose response data to sigmoidal curve fitting equation using GraphPad Prism software V5. To identify compounds that inhibit CDK7 irreversibly, time depended inhibition studies were carried by pre-incubating compound with the enzyme at three time points (20, 60 and 180 min) and carrying out assay as described above.
Measurement: IC50 > 1000 nM (pChEMBL 6)
Descriptors: MW 560.7, ALogP 4.26, HBA 9, HBD 3, PSA 125.78, QED 0.33
Compound (SMILES): COC/C=C/C(=O)N1CCC(C(=O)Nc2cccc(CNc3nc(NC4CCOCC4)nc4c(C(C)C)cnn34)c2)C1
InChIKey: SDHIXASQHYFOME-VMPITWQZSA-N
Target: CDK7/Cyclin H/MNAT1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P50613
Assay: Biochemical Assay for CDK7: The ability of compounds to inhibit CDK7 kinase activity was tested in a TR-FRET assay using 5 nM of CDK7/CycH/MNAT1 obtained from Invitrogen, USA. Test compounds were pre-incubated with the kinase at room temperature for 60 min. After incubation, substrate mix [100 nM Ultra-light MBP (Perkin Elmer, USA) and 1 mM ATP (Sigma)] was added. The above reaction was stopped by the addition of 40 mM EDTA after 60 minutes of kinase reaction. 1 nM Eu-labelled antiphospho-MBP antibody [Perkin Elmer, USA] was added, mixed well and the fluorescence emission at 615 nm and 665 nm [excitation at 340 nm] was measured. The final DMSO concentration in the assay was 1%. For IC50 determination, appropriate concentrations were made by ⅓rd serial dilutions of 10 mM DMSO stock solution of test compound. All the fluorescence measurements were made in a Victor 3 Multilabel Counter [Perkin Elmer, USA]. The IC50 was determined by fitting the dose response data to sigmoidal curve fitting equation using GraphPad Prism software V5. To identify compounds that inhibit CDK7 irreversibly, time depended inhibition studies were carried by pre-incubating compound with the enzyme at three time points (20, 60 and 180 min) and carrying out assay as described above.
Measurement: IC50 = 650 nM (pChEMBL 6.190000057220459)
Descriptors: MW 576.7, ALogP 3.44, HBA 10, HBD 3, PSA 135.01, QED 0.29
Compound (SMILES): COc1nc(O[C@H]2CCc3c(-c4ccccc4)cccc32)ccc1CNCCO
InChIKey: XCQQKJDPFVDCJW-QFIPXVFZSA-N
Target: Programmed cell death protein 1/Programmed cell death 1 ligand 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15116
Assay: Inhibition of PD-1/PD-L1 (unknown origin) protein-protein interaction incubated for 15 mins by TR-FRET assay
Measurement: IC50 = 24.4 nM (pChEMBL 7.610000133514404)
Descriptors: MW 390.48, ALogP 3.91, HBA 5, HBD 2, PSA 63.61, QED 0.57
Compound (SMILES): CCNCc1nnnn1/C=C/c1cccc(-c2ccccc2)c1C
InChIKey: WDSZHUIPBINVDD-OUKQBFOZSA-N
Target: Programmed cell death protein 1/Programmed cell death 1 ligand 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15116
Assay: Antagonist activity at human PD-1/PD-L1 interaction measured after 1 hr by HTRF assay
Measurement: IC50 = 408 nM (pChEMBL 6.389999866485596)
Descriptors: MW 319.41, ALogP 3.39, HBA 5, HBD 1, PSA 55.63, QED 0.76
Compound (SMILES): N#Cc1cccc(COc2cc(OCc3cccc(-c4ccccc4F)c3Cl)ccc2CN2CCC(O)C2)c1
InChIKey: GMZMVHUXVQFFMB-UHFFFAOYSA-N
Target: Programmed cell death protein 1/Programmed cell death 1 ligand 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15116
Assay: Inhibition of PD-1/PD-L1 interaction (unknown origin) incubated for 1 hr by HTRF assay
Measurement: IC50 = 19200 nM (pChEMBL 4.71999979019165)
Descriptors: MW 543.04, ALogP 6.74, HBA 5, HBD 1, PSA 65.72, QED 0.25
Compound (SMILES): COc1cc(-c2cccc(-c3ccc4c(c3)OCCO4)c2Cl)ccc1CN1CCCC(C(=O)NO)C1
InChIKey: ZNGLTXDZPALGIC-UHFFFAOYSA-N
Target: Programmed cell death protein 1/Programmed cell death 1 ligand 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15116
Assay: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay
Measurement: IC50 = 1.09 nM (pChEMBL 8.960000038146973)
Descriptors: MW 509, ALogP 5.17, HBA 6, HBD 2, PSA 80.26, QED 0.35
Compound (SMILES): COc1cc2c(cc1CNCCO)C(=O)N(c1cccc(-c3ccccc3)c1C)C2=O
InChIKey: KHBBFJBCQWWIFX-UHFFFAOYSA-N
Target: Programmed cell death protein 1/Programmed cell death 1 ligand 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15116
Assay: Inhibition of europium-labeled PD-1/biotinylated PD-L1 interaction (unknown origin) preincubated for 15 mins with PD-L1 followed by PD-1 addition and measured after 90 mins by TR-FRET assay
Measurement: IC50 = 15.6 nM (pChEMBL 7.809999942779541)
Descriptors: MW 416.48, ALogP 3.55, HBA 5, HBD 2, PSA 78.87, QED 0.45
Compound (SMILES): Cl.N[C@H]1CCN(c2c3c(nc4ccc(-c5ccnc(NC(=O)C6CCC6)c5)cc24)CCCCC3)C1
InChIKey: YFMOIJRIGRVZKR-BOXHHOBZSA-N
Target: CDK2/Cyclin A2 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24941
Assay: Inhibition of human full length CDK2/CyclinA2 by ADP-Glo kinase assay
Measurement: IC50 = 10.7 nM (pChEMBL 7.96999979019165)
Descriptors: MW 455.61, ALogP 4.84, HBA 5, HBD 2, PSA 84.14, QED 0.55
Compound (SMILES): N#Cc1cccc(COc2cc(OCc3cccc(-c4ccccc4F)c3Cl)ccc2CN2CC(C(=O)O)C2)c1
InChIKey: ZVBSLQNFWDZLJU-UHFFFAOYSA-N
Target: Programmed cell death protein 1/Programmed cell death 1 ligand 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15116
Assay: Inhibition of PD-1/PD-L1 interaction (unknown origin) incubated for 1 hr by HTRF assay
Measurement: IC50 = 33600 nM (pChEMBL 4.46999979019165)
Descriptors: MW 557.02, ALogP 6.69, HBA 5, HBD 1, PSA 82.79, QED 0.23
Compound (SMILES): COc1cc(-c2cccc(-c3ccc4c(c3)OCCO4)c2Cl)ccc1CN1CCCC1C(=O)NCCO
InChIKey: ZEOPQMVZEJVXTO-UHFFFAOYSA-N
Target: Programmed cell death protein 1/Programmed cell death 1 ligand 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15116
Assay: Inhibition of human PD-1/PDL1 interaction incubated for 1 hr by HTRF assay
Measurement: IC50 < 0.5 nM (pChEMBL 9.300999641418457)
Descriptors: MW 523.03, ALogP 4.53, HBA 6, HBD 2, PSA 80.26, QED 0.45
Compound (SMILES): CC(C)c1cc(N[C@H]2C[C@H](N)C2)n2nccc2n1
InChIKey: CDVYLHGEJHJTQG-MGCOHNPYSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: Inhibition of human CDK9/Cyclin T1 preincubated for 20 mins followed by 32P-ATP addition and measured after 2 hrs
Measurement: IC50 = 25 nM (pChEMBL 7.599999904632568)
Descriptors: MW 245.33, ALogP 1.75, HBA 5, HBD 2, PSA 68.24, QED 0.86
Compound (SMILES): COc1cc2nc(NCCCN(C)C)nc(N(C)C)c2cc1OC
InChIKey: OGNSGOBRJCYTGK-UHFFFAOYSA-N
Target: LSD1/CoREST complex (PROTEIN COMPLEX), Homo sapiens
UniProt: O60341
Assay: Inhibition of human LSD1-CoREST expressed in Escherichia coli assessed as dissociation constant
Measurement: Kd = 7780 nM (pChEMBL 5.110000133514404)
Descriptors: MW 333.44, ALogP 2.08, HBA 7, HBD 1, PSA 62.75, QED 0.74
Compound (SMILES): CN(C)C(C)(C)C(=O)Nc1cc(F)c2c(c1)CC(CNCCC1CN(c3cnc4c(n3)NC(=O)CO4)C(=O)O1)C2
InChIKey: ATNSPUQRDBKCOK-UHFFFAOYSA-N
Target: DNA gyrase (PROTEIN COMPLEX), Escherichia coli
UniProt: P0AES6
Assay: Inhibition of Escherichia coli DNA gyrase incubated for 80 mins by Transcreener ADP2 FI assay
Measurement: IC50 = 43 nM (pChEMBL 7.369999885559082)
Descriptors: MW 555.61, ALogP 1.95, HBA 9, HBD 3, PSA 138.02, QED 0.4
Compound (SMILES): CC[C@H](C)c1cc(N[C@H]2CC[C@H](N)C2)n2nccc2n1
InChIKey: FXIBYHMMHYQWFQ-SRVKXCTJSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: Inhibition of human CDK9/Cyclin T1 preincubated for 20 mins followed by 32P-ATP addition and measured after 2 hrs
Measurement: IC50 = 10 nM (pChEMBL 8)
Descriptors: MW 273.38, ALogP 2.53, HBA 5, HBD 2, PSA 68.24, QED 0.9
Compound (SMILES): CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](OC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)N3CCc4cc(Cn5nc(-c6ccc7oc(N)nc7c6)c6c(N)ncnc65)ccc4C3)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
InChIKey: CHLJLODIXLIFHL-VPQIPYMUSA-N
Target: mTORC1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q8N122
Assay: Inhibition of mTORC1 in human MDA-MB-468 cells assessed as reduction in P70S6K phosphorylation at Thr389 by AlphaLISA assay
Measurement: IC50 = 0.19 nM (pChEMBL 9.720000267028809)
Descriptors: MW 1776.14
Compound (SMILES): CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](OCCCCc3cn(CCOCCOCCOCCOCCOCCC(=O)NCCCCn4nc(-c5ccc6oc(N)nc6c5)c5c(N)ncnc54)nn3)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
InChIKey: SSCGARDPFCUSOD-STZJFXDCSA-N
Target: mTORC1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q8N122
Assay: Inhibition of mTORC1 in human MDA-MB-468 cells assessed as reduction in P70S6K phosphorylation at Thr389 by AlphaLISA assay
Measurement: IC50 = 0.37 nM (pChEMBL 9.430000305175781)
Descriptors: MW 1650.03
Compound (SMILES): CC(C)c1cc(N[C@H]2C[C@H](NS(C)(=O)=O)C2)n2nccc2n1
InChIKey: BALSFXPMGHRTOT-XYPYZODXSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: Inhibition of human CDK9/Cyclin T1 preincubated for 20 mins followed by 32P-ATP addition and measured after 2 hrs
Measurement: IC50 = 74 nM (pChEMBL 7.130000114440918)
Descriptors: MW 323.42, ALogP 1.34, HBA 6, HBD 2, PSA 88.39, QED 0.87
Compound (SMILES): COc1cc2c(cc1CNCC(=O)O)C(=O)N(c1cccc(-c3ccccc3)c1C)C2=O
InChIKey: URVCDVIRMKGENT-UHFFFAOYSA-N
Target: Programmed cell death protein 1/Programmed cell death 1 ligand 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15116
Assay: Inhibition of europium-labeled PD-1/biotinylated PD-L1 interaction (unknown origin) preincubated for 15 mins with PD-L1 followed by PD-1 addition and measured after 90 mins by TR-FRET assay
Measurement: IC50 = 35.9 nM (pChEMBL 7.449999809265137)
Descriptors: MW 430.46, ALogP 3.65, HBA 5, HBD 2, PSA 95.94, QED 0.56
Compound (SMILES): C#CCOC(=O)NCCCC[C@H](NCc1cc(Cl)c(OCc2cccc(-c3ccc4c(c3)OCCO4)c2C)cc1OCc1ccnc(C#N)c1)C(=O)O
InChIKey: LLALFKPOYVMQAR-UMSFTDKQSA-N
Target: Programmed cell death protein 1/Programmed cell death 1 ligand 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15116
Assay: Inhibition of PD-1 binding to human PD-L1 by HTRF assay
Measurement: IC50 = 3.7 nM (pChEMBL 8.430000305175781)
Descriptors: MW 739.23, ALogP 6.58, HBA 10, HBD 3, PSA 161.26, QED 0.08
Compound (SMILES): CC[C@H](C)[C@@H]1NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)[C@@H]2CCCN2C(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]2CSSC[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc3ccc(O)cc3)C(=O)N2)CSSC[C@@H](C(=O)N[C@H](C(=O)O)C(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H]([C@@H](C)O)NC1=O
InChIKey: WVTSQWOOLRWWRL-ZPJHLRTLSA-N
Target: Nicotinic acetylcholine receptor alpha9/alpha10 (PROTEIN COMPLEX), Rattus norvegicus
UniProt: P43144
Assay: Antagonist activity at rat alpha9alpha10 nACh receptor expressed in Xenopus oocyte assessed as inhibition of acetylcholine-induced response at -70 mV holding potential by voltage-clamp based electrophysiological assay
Measurement: IC50 = 27 nM (pChEMBL 7.570000171661377)
Descriptors: MW 3436.96
Compound (SMILES): COc1c(NCc2ccc(OCc3cccc(C#N)c3)c(CNCCNC(C)=O)c2)cccc1-c1ccc2ccccc2c1
InChIKey: ANFRFZYLQYVVJE-UHFFFAOYSA-N
Target: Programmed cell death protein 1/Programmed cell death 1 ligand 1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q15116
Assay: Inhibition of PD-1/PD-L1 interaction (unknown origin) incubated for 1 hr by HTRF assay
Measurement: IC50 > 32000 nM (pChEMBL 4.494999885559082)
Descriptors: MW 584.72, ALogP 6.8, HBA 6, HBD 3, PSA 95.41, QED 0.13
Compound (SMILES): Cc1ccccc1NC(=O)Nc1ccc(C[C@H]2NC(=O)C[C@H](C(=O)O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CC(C)C)NC2=O)cc1
InChIKey: FXYDXLJEJBXFBD-WTKZALBSSA-N
Target: Integrin alpha-4/beta-1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P13612
Assay: Agonist activity at alpha4beta1 integrin receptor in human Jurkat E6.1 cells assessed as inhibition of fibronectin-induced cell adhesion pre-incubated for 30 mins followed by 30 mins incubation in fibronectin coated wells by fluorescence plate reader assay
Measurement: EC50 = 40.9 nM (pChEMBL 7.389999866485596)
Descriptors: MW 737.81, ALogP 1.27, HBA 8, HBD 9, PSA 261.23, QED 0.17
Compound (SMILES): CN(C)C(=O)[C@@H](NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1)c1cccc(C2CC2)c1
InChIKey: SUOXNBOKLNOYRA-DEOSSOPVSA-N
Target: NKGD2-MICA (PROTEIN COMPLEX), Homo sapiens
UniProt: P26718
Assay: Inhibition of NKG2D (unknown origin)/MICA (unknown origin) protein-protein interaction by cell-based TR-FRET assay
Measurement: IC50 = 1800 nM (pChEMBL 5.75)
Descriptors: MW 466.5, ALogP 5.81, HBA 2, HBD 1, PSA 49.41, QED 0.5