lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CC(CO)C4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
InChIKey: MZMABECMGLNFPJ-UHFFFAOYSA-N
Target: Hepatocyte growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P08581
Assay: Enzyme Assay: The affinity of compound binding to wild type and mutant human MET kinases is measured using Invitrogen's LanthaScreen Eu Kinase Binding technology. Briefly, GST-tagged recombinant human MET kinase domain from Signal Chem (see Table 8 below for concentration in assay) is incubated with 50 nM Alexa-Fluor® Tracer 236 (Invitrogen Cat No. PR9078A) and 2 nM Europium-anti-GST (Invitrogen Cat. No. A151 6) along with test compound in a buffer consisting of 25 mM HEPES, pH 7.4, 10 mM MgCl2, 0.01% Triton X-100, 1 mM DTT, and 2% DMSO. Compounds are typically prepared in a three-fold serial dilution in DMSO and added to the assay to give the appropriate final concentration. After a 60-minute incubation at 22° C., the reaction is measured using a PerkinElmer EnVision multimode plate reader via TR-FRET dual wavelength detection, and the percent of control (POC) calculated using a ratiometric emission factor. 100 POC is determined using no test compounds and 0 POC is determined using a concentration of control compound that completely inhibits the enzyme
Measurement: IC50 = 3.9 nM (pChEMBL 8.40999984741211)
Descriptors: MW 559.53, ALogP 4.01, HBA 9, HBD 4, PSA 147.05, QED 0.22
Compound (SMILES): O=C(Nc1ccc(Oc2ccnc3[nH]nc(NC4CC(CO)C4)c23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
InChIKey: MZMABECMGLNFPJ-UHFFFAOYSA-N
Target: Hepatocyte growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P08581
Assay: Enzyme Assay: The affinity of compound binding to wild type and mutant human MET kinases is measured using Invitrogen's LanthaScreen Eu Kinase Binding technology. Briefly, GST-tagged recombinant human MET kinase domain from Signal Chem (see Table 8 below for concentration in assay) is incubated with 50 nM Alexa-Fluor® Tracer 236 (Invitrogen Cat No. PR9078A) and 2 nM Europium-anti-GST (Invitrogen Cat. No. A151 6) along with test compound in a buffer consisting of 25 mM HEPES, pH 7.4, 10 mM MgCl2, 0.01% Triton X-100, 1 mM DTT, and 2% DMSO. Compounds are typically prepared in a three-fold serial dilution in DMSO and added to the assay to give the appropriate final concentration. After a 60-minute incubation at 22° C., the reaction is measured using a PerkinElmer EnVision multimode plate reader via TR-FRET dual wavelength detection, and the percent of control (POC) calculated using a ratiometric emission factor. 100 POC is determined using no test compounds and 0 POC is determined using a concentration of control compound that completely inhibits the enzyme
Measurement: IC50 = 2.2 nM (pChEMBL 8.65999984741211)
Descriptors: MW 559.53, ALogP 4.01, HBA 9, HBD 4, PSA 147.05, QED 0.22
Compound (SMILES): Cn1c(=O)n(CC(=O)N2CC(F)(F)C2)c2cc(-c3ccc(F)c(C(F)F)c3)cnc21
InChIKey: XENKVFPNHPYUKN-UHFFFAOYSA-N
Target: Glutamate NMDA receptor; GRIN1/GRIN2B (PROTEIN COMPLEX), Homo sapiens
UniProt: Q13224
Assay: Biological Assay (standard): NMDA receptors are ion channels that are highly permeable to Ca2+ ions, rendering it possible to monitor NMDA receptor function using cell-based calcium flux assay. In this assay, co-agonists glutamate and glycine are added to cells heterologously expressing human GluN1/GluN2B NMDA receptors to initiate cellular Ca2+ influx. The time course of the changes in intracellular calcium is measured using a fluorescent dye and a FLIPR (Fluorometric Imaging Plate Reader) device.Twenty four hours before measurements, the expression of the NMDA receptors in the stable cell line is induced with Tet-On inducible system in the presence of a non-selective NMDA receptor blocker. On the day of the experiment, cell culture media is carefully washed and the cells are loaded with Calcium 5 Dye Kit (Molecular Devices) in dye loading buffer containing 137 mM NaCl, 4 mM KCl, 2 mM CaCl2), 0.5 mM MgCl2, 10 mM HEPES and 5 mM D-glucose; pH 7.4. After 1 h incubation at the room temperature, the dye is washed away with the assay buffer (137 mM NaCl, 4 mM KCl, 2 mM CaCl2), 0.01 mM EDTA, 10 mM HEPES and 5 mM D-glucose; pH 7.4) In the FLIPR TETRA reader, various concentrations of the test compounds are added to the cells for 5 min while fluorescence is monitored to detect potential agonist activity. Next, co-agonists, glutamate and glycine are added for another 5 minutes. The concentration of glutamate corresponding to ~EC40 used to maximize the assay's signal window and ability to detect NMDA receptor antagonists and negative allosteric modulators. A saturating concentration (10 μM) of glycine is also present in the assay. A non-selective NMDA receptor antagonist, (+)MK-801 is used as a positive control for antagonist activity. The fluorescent signal in the presence of test compounds is quantified and normalized to the signal defined by the appropriate control wells.
Measurement: IC50 = 51 nM (pChEMBL 7.289999961853027)
Descriptors: MW 426.35, ALogP 2.96, HBA 5, HBD 0, PSA 60.13, QED 0.6
Compound (SMILES): CN1CCN(S(=O)(=O)c2ccc(Nc3ncc4cc5n(c4n3)C3(CCCCC3)C(=O)NC5O)cc2)CC1
InChIKey: CXMKIWPGGSLHRE-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 2/cyclin E1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24941
Assay: CDK Inhibition In Vitro Assay: Selected compounds disclosed herein were tested in kinase assays by Nanosyn (Santa Clara, Calif.) to determine their inhibitory effect on these CDKs. The assays were performed using microfluidic kinase detection technology (Caliper Assay Platform). The compounds were tested in 12-point dose-response format in singlicate at Km for ATP. Specifics of each assay are as described below:CDK1/Cyclin B1: Enzyme concentration: 0.08 nM; ATP concentration: 40 μM; Incubation time: 3 hr. CDK2/Cyclin A: Enzyme concentration: 0.1 nM; ATP concentration: 50 μM; Incubation time: 3 hr. CDK2/Cyclin E: Enzyme concentration: 0.15 nM; ATP concentration: 100 μM; Incubation time: 3 hr. CDK4/Cyclin D1: Enzyme concentration: 1 nM; ATP concentration: 200 μM; Incubation time: 3 hr. CDK6/Cyclin D3: Enzyme concentration: 2 nM; ATP concentration: 300 μM; Incubation time: 3 hr. CDK9/Cyclin T1: Enzyme concentration: 5 nM; ATP concentration: 10 μM; Incubation time: 17 hr.
Measurement: IC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 525.64, ALogP 1.89, HBA 9, HBD 3, PSA 132.69, QED 0.47
Compound (SMILES): COc1ccc(Nc2cc(-c3ccccc3OC)ncn2)cc1C(N)=O
InChIKey: ZEMCPOSFLUAYMK-UHFFFAOYSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: In Vitro CDK9/CyclinT Assay: The activity of the compounds described in the present invention can be determined by measuring the phosphorylation of a fluorescently-labeled peptide by human CDK9/CyclinT kinase complex by fluorescent polarization using a commercially available IMAP Screening Express Assay Kit (Molecular devices).Test compounds were diluted in 100% DMSO to 5 mM stock concentration, then further dilutions were made in H2O or 100% DMSO to desirable concentrations.Each reaction consisted of 5 nM enzyme: CDK9/CyclinT (Proqinase cat#0371-0345-1), 400 nM TAMRA-Rbtide (synthetic 15-mer peptide derived from human retinoblastoma tumor suppressor protein labeled with TAMRA dye, Genecust Europe), 12 μM ATP (=Kmapp, Sigma-Aldrich) and kinase buffer: 20 mM MOPS pH 7 (Sigma-Aldrich), 1 mM DTT (Sigma-Aldrich), 10 mM MgCl2 (Sigma-Aldrich), 0.01% Tween 20 (Sigma-Aldrich).For each reaction, 4 or 6 μl containing TAMRA-Rbtide, ATP and kinase buffer were combined with 2 μl diluted compound in H2O or 0.028 μl compound in 100% DMSO. The kinase reaction was started by the addition of 2 μl diluted enzyme. The reaction was allowed to run for 1 hour at room temperature. The reaction was stopped by adding 15 μl IMAP beads (1:400 beads in progressive (100% buffer A) 1× buffer). After an additional 1 hour, fluorescent polarization (Ex: 550-10 nm, Em: 590-10 nm, Dich: 561 nm) was measured using an Analyst GT (Molecular devices).
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 350.38, ALogP 3, HBA 6, HBD 2, PSA 99.36, QED 0.71
Compound (SMILES): CN(C)C(=O)Cn1c(=O)n(C)c2ncc(-c3csc(C(F)(F)F)c3)cc21
InChIKey: CLQCUNFBUZQZHI-UHFFFAOYSA-N
Target: Glutamate NMDA receptor; GRIN1/GRIN2B (PROTEIN COMPLEX), Homo sapiens
UniProt: Q13224
Assay: Biological Assay (standard): NMDA receptors are ion channels that are highly permeable to Ca2+ ions, rendering it possible to monitor NMDA receptor function using cell-based calcium flux assay. In this assay, co-agonists glutamate and glycine are added to cells heterologously expressing human GluN1/GluN2B NMDA receptors to initiate cellular Ca2+ influx. The time course of the changes in intracellular calcium is measured using a fluorescent dye and a FLIPR (Fluorometric Imaging Plate Reader) device.Twenty four hours before measurements, the expression of the NMDA receptors in the stable cell line is induced with Tet-On inducible system in the presence of a non-selective NMDA receptor blocker. On the day of the experiment, cell culture media is carefully washed and the cells are loaded with Calcium 5 Dye Kit (Molecular Devices) in dye loading buffer containing 137 mM NaCl, 4 mM KCl, 2 mM CaCl2), 0.5 mM MgCl2, 10 mM HEPES and 5 mM D-glucose; pH 7.4. After 1 h incubation at the room temperature, the dye is washed away with the assay buffer (137 mM NaCl, 4 mM KCl, 2 mM CaCl2), 0.01 mM EDTA, 10 mM HEPES and 5 mM D-glucose; pH 7.4) In the FLIPR TETRA reader, various concentrations of the test compounds are added to the cells for 5 min while fluorescence is monitored to detect potential agonist activity. Next, co-agonists, glutamate and glycine are added for another 5 minutes. The concentration of glutamate corresponding to ~EC40 used to maximize the assay's signal window and ability to detect NMDA receptor antagonists and negative allosteric modulators. A saturating concentration (10 μM) of glycine is also present in the assay. A non-selective NMDA receptor antagonist, (+)MK-801 is used as a positive control for antagonist activity. The fluorescent signal in the presence of test compounds is quantified and normalized to the signal defined by the appropriate control wells.
Measurement: IC50 = 19 nM (pChEMBL 7.71999979019165)
Descriptors: MW 384.38, ALogP 2.57, HBA 6, HBD 0, PSA 60.13, QED 0.7
Compound (SMILES): Cc1cnc([C@@H](C)NC(=O)c2cc(OC[C@@H]3CCCO3)cc(-c3ncc(C)s3)c2)cn1
InChIKey: MANPQCKCYFRFOG-APWZRJJASA-N
Target: P2X2/P2X3 heterotrimeric receptor (PROTEIN COMPLEX), Homo sapiens
UniProt: P56373
Assay: Intracellular Calcium Measurement to Assess Antagonist Activity : A fluorescent imaging plate reader (FLEX/FLIPR station; Molecular Devices) was used to monitor intracellular calcium levels using the calcium-chelating dye Fluo-4 (Molecular Probes). The excitation and emission wavelengths used to monitor fluorescence were 470-495 nm and 515-575 nm, respectively. Cells expressing purinergic receptors P2X3 (human) or P2X2/3 (human) were plated at a density of 15,000 cells/well in collagen-coated 384-well plates approximately 20 hours before beginning the assay. On the day of the assay, 20 μl of loading buffer (Hank's balanced salt solution, 20 mM HEPES, 0.5 mM CaCl2, 0.5 mM MgCl2, 0.1% BSA, 5 mM probenecid, 10 mM D-glucose monohydrate, 2 μM Fluo-4, and 5 units/mL, hexokinase, pH=7.4) was added and cells dye-loaded for 90 min at 37° C. The dye supernatant was removed and replaced with 45 μl probenecid buffer (Hank's balanced salt solution, 20 mM HEPES, 0.5 mM CaCl2, 0.5 mM MgCl2, 0.1% BSA, 5 mM probenecid, 10 mM D-glucose monohydrate, pH=7.4). The test compound was added in a volume of 5 μl and allowed to incubate for 30 min at 37° C. The final assay DMSO concentration is 1%.The agonist, α,β-Me-ATP, was added in a volume of 20 μl at a concentration representing the EC80 value. The fluorescence was measured for an interval of 90 sec at 2 sec intervals and analyzed based on the increase in peak relative fluorescence units (RFU) compared to the basal fluorescence. Peak fluorescence was used to determine the response to agonist obtained at each concentration of test compound by the following equation: % Response=100*(RFU(test compound)−RFU(control))/(RFU(DMSO)−RFU(control)).
Measurement: IC50 = 2840 nM (pChEMBL 5.550000190734863)
Descriptors: MW 438.55, ALogP 4.27, HBA 7, HBD 1, PSA 86.23, QED 0.59
Compound (SMILES): COCc1cnc(OCc2cn(-c3ccc(F)c(C(F)(F)F)c3)nn2)nc1
InChIKey: ZODDYVLEFWKLKN-UHFFFAOYSA-N
Target: Glutamate NMDA receptor; GRIN1/GRIN2B (PROTEIN COMPLEX), Homo sapiens
UniProt: Q13224
Assay: NMDA receptor FLIPR assay: NMDA receptors are ion channels that are highly permeable to Ca2+ ions, rendering it possible to monitor NMDA receptor function using cell-based calcium flux assay. In this assay, co-agonists glutamate and glycine are added to cells heterologously expressing human GluN1/GluN2B NMDA receptors to initiate cellular Ca2+ influx. The time course of the changes in intracellular calcium is measured using a fluorescent dye and a FLIPR (Fluorometric Imaging Plate Reader) device.Twenty four hours before measurements, the expression of the NMDA receptors in the stable cell line is induced with Tet-On inducible system in the presence of a non-selective NMDA receptor blocker. On the day of the experiment, cell culture media is carefully washed and the cells are loaded with Calcium 5 Dye Kit (Molecular Devices) in dye loading buffer containing 149 mM NaCl, 4 mM KCl, 2 mM CaCl2, and 1.5 mM MgCl2, 10 mM HEPES and 5 mM D-glucose; pH 7.4. After 1 h incubation at the room temperature, the dye is washed away with the assay buffer (149 mM NaCl (standard assay) or 150 mM (HTS assay), 4 mM KCl (standard assay) or 3 mM (HTS assay), 2 mM CaCl2, 0.01 mM EDTA, 10 mM HEPES and 5 mM D-glucose; pH 7.4) In the FLIPR TETRA reader, various concentrations of the test compounds are added to the cells for 5 min while fluorescence is monitored to detect potential agonist activity. Next, co-agonists, glutamate and glycine are added for another 5 minutes. The concentration of glutamate corresponding to EC80 (standard assay) or EC40 (HTS assay) is used to maximize the assay's signal window or the ability to detect NMDA receptor antagonists and negative allosteric modulators, respectively. A saturating concentration (10 μM) of glycine is also present in the assay. A non-selective NMDA receptor antagonist, (+)MK-801 is used as a positive control for antagonist activity. The fluorescent signal in the presence of test compounds is quantified and normalized to the signal defined by the appropriate control wells.
Measurement: IC50 = 71 nM (pChEMBL 7.150000095367432)
Descriptors: MW 383.31, ALogP 2.94, HBA 7, HBD 0, PSA 74.95, QED 0.61
Compound (SMILES): CC(=O)c1c(C)c2cnc(N[C@@H]3CCOC[C@H]3O)nc2n(C2CCCC2)c1=O
InChIKey: YVGUVHSVOMWPCR-HZPDHXFCSA-N
Target: CDK6/cyclin D3 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q00534
Assay: CDK6/Cyclin D3 Mobility Shift Assay: The purpose of the CDK6/Cyclin D3 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. CDK6/Cyclin D3 catalyzes the production of ADP from ATP that accompanies the phosphoryl transfer to the substrate peptide 5-FAM-Dyrktide 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), 2% glycerol, 10 mM MgCl2, 1 mM DTT, 3.5 mM ATP, 0.005% Tween 20 (TW-20), 3 μM 5-FAM-Dyrktide, 4 nM activated CDK6/Cyclin D3 in 40 mM HEPES buffer at pH 7.5.
Measurement: Ki = 1.2 nM (pChEMBL 8.920000076293945)
Descriptors: MW 386.45, ALogP 1.98, HBA 8, HBD 2, PSA 106.34, QED 0.77
Compound (SMILES): CNS(=O)(=O)N1CCC(Nc2ncc3ccc(=O)n([C@@H]4C[C@@H](O)CC[C@H]4F)c3n2)CC1
InChIKey: COWPKYBSZGEQGW-ARFHVFGLSA-N
Target: CDK6/cyclin D1 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q00534
Assay: CDK6/Cyclin D1 Mobility Shift Assay: The purpose of the CDK6/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. CDK6/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:2). 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, 2 mM ATP, 0.005% Tween 20 (TW-20), 3 μM 5-FAM-Dyrktide, 3 nM (active sites) CDK6/Cyclin D1 in 40 mM HEPES buffer at pH 7.5.Inhibitor Ki determinations for non-phosphorylated CDK6/CyclinD1 (LJIC-2003A2/1865) were initiated with the addition of ATP (50 μL final reaction volume), following a twelve minute pre-incubation of enzyme and inhibitor at 22° C. in the reaction mix. The reaction was stopped after 35 minutes by the addition of 50 μL of 25 mM EDTA. Ki determinations were made from a plot of the fractional velocity as a function of inhibitor concentration fit to the Morrison equation with the enzyme concentration as a variable.
Measurement: Ki = 18.3 nM (pChEMBL 7.739999771118164)
Descriptors: MW 454.53, ALogP 0.56, HBA 8, HBD 3, PSA 129.45, QED 0.6
Compound (SMILES): CC(=O)N[C@@H]1CCC[C@H](C(=O)Nc2cc(-c3cc(F)c4nn(C)c(C(C)(O)C(F)(F)F)c4c3)c(C)cn2)C1
InChIKey: CEERPSVTLJOQDZ-OCWAHVNLSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: CDK4/CyclinD1 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 and used in IC50 determination. Recombinant protein complex CDK4/Cyclin D1, expressed from insect cell, was purchased from ProQinase. Testing compounds were dissolved in DMSO at 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) to make a 9.9 μL of reaction mixture. After 20 minutes preincubation at room temperature, 0.1 μL MgCl2(10 mM final) was added to initiate the reaction. Following a 45 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), LANCE Ultra Europium-anti-P-4E-BP1 (Perkinelmer, TRF0216-D), 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 = 1.97 nM (pChEMBL 8.710000038146973)
Descriptors: MW 535.54, ALogP 4.49, HBA 6, HBD 3, PSA 109.14, QED 0.42
Compound (SMILES): CC#CCOc1cc(C(=O)N[C@H](C)c2cnc(C(F)(F)F)nc2)cc(-c2ncc(C)s2)c1
InChIKey: XSZOYFWYESZINQ-CQSZACIVSA-N
Target: P2X2/P2X3 heterotrimeric receptor (PROTEIN COMPLEX), Homo sapiens
UniProt: P56373
Assay: Intracellular Calcium Measurement to Assess Antagonist Activity : A fluorescent imaging plate reader (FLEX/FLIPR station; Molecular Devices) was used to monitor intracellular calcium levels using the calcium-chelating dye Fluo-4 (Molecular Probes). The excitation and emission wavelengths used to monitor fluorescence were 470-495 nm and 515-575 nm, respectively. Cells expressing purinergic receptors P2X3 (human) or P2X2/3 (human) were plated at a density of 15,000 cells/well in collagen-coated 384-well plates approximately 20 hours before beginning the assay. On the day of the assay, 20 μl of loading buffer (Hank's balanced salt solution, 20 mM HEPES, 0.5 mM CaCl2, 0.5 mM MgCl2, 0.1% BSA, 5 mM probenecid, 10 mM D-glucose monohydrate, 2 μM Fluo-4, and 5 units/mL, hexokinase, pH=7.4) was added and cells dye-loaded for 90 min at 37° C. The dye supernatant was removed and replaced with 45 μl probenecid buffer (Hank's balanced salt solution, 20 mM HEPES, 0.5 mM CaCl2, 0.5 mM MgCl2, 0.1% BSA, 5 mM probenecid, 10 mM D-glucose monohydrate, pH=7.4). The test compound was added in a volume of 5 μl and allowed to incubate for 30 min at 37° C. The final assay DMSO concentration is 1%.The agonist, α,β-Me-ATP, was added in a volume of 20 μl at a concentration representing the EC80 value. The fluorescence was measured for an interval of 90 sec at 2 sec intervals and analyzed based on the increase in peak relative fluorescence units (RFU) compared to the basal fluorescence. Peak fluorescence was used to determine the response to agonist obtained at each concentration of test compound by the following equation: % Response=100*(RFU(test compound)−RFU(control))/(RFU(DMSO)−RFU(control)).
Measurement: IC50 = 383 nM (pChEMBL 6.420000076293945)
Descriptors: MW 460.48, ALogP 4.82, HBA 6, HBD 1, PSA 77, QED 0.53
Compound (SMILES): CN1CCN(S(=O)(=O)c2ccc(Nc3ncc4cc5n(c4n3)C3(CCCCC3)C(=O)NC5O)cc2)CC1
InChIKey: CXMKIWPGGSLHRE-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 4/cyclin D1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P11802
Assay: CDK Inhibition In Vitro Assay: Selected compounds disclosed herein were tested in kinase assays by Nanosyn (Santa Clara, Calif.) to determine their inhibitory effect on these CDKs. The assays were performed using microfluidic kinase detection technology (Caliper Assay Platform). The compounds were tested in 12-point dose-response format in singlicate at Km for ATP. Specifics of each assay are as described below:CDK1/Cyclin B1: Enzyme concentration: 0.08 nM; ATP concentration: 40 μM; Incubation time: 3 hr. CDK2/Cyclin A: Enzyme concentration: 0.1 nM; ATP concentration: 50 μM; Incubation time: 3 hr. CDK2/Cyclin E: Enzyme concentration: 0.15 nM; ATP concentration: 100 μM; Incubation time: 3 hr. CDK4/Cyclin D1: Enzyme concentration: 1 nM; ATP concentration: 200 μM; Incubation time: 3 hr. CDK6/Cyclin D3: Enzyme concentration: 2 nM; ATP concentration: 300 μM; Incubation time: 3 hr. CDK9/Cyclin T1: Enzyme concentration: 5 nM; ATP concentration: 10 μM; Incubation time: 17 hr.
Measurement: IC50 = 113 nM (pChEMBL 6.949999809265137)
Descriptors: MW 525.64, ALogP 1.89, HBA 9, HBD 3, PSA 132.69, QED 0.47
Compound (SMILES): CN1CCN(Cc2cc(C(=O)Nc3ccc4c(c3)CN(c3cncnc3)CC4)cc(C(F)(F)F)c2)CC1
InChIKey: ITUXUBYGLUMEOU-UHFFFAOYSA-N
Target: Bcr/Abl fusion protein (CHIMERIC PROTEIN), Homo sapiens
UniProt: P00519
Assay: Lantha Screen Eu Kinase Activity Assay: The effects of compounds on the kinases DDR1 and DDR2 were assessed by using a Lantha Screen Eu kinase activity assay technology (Invitrogen, USA). Kinase reactions are performed in a 10 uL volume in low-volume 384-well plates. The kinases in reaction buffer consist of 50 mM HEPES pH 7.5, 0.01% BRU-35, 10 mM MgCl2, and 1 mM EGTA, the concentration of Fluorescein-Poly GAT substrate (Invitrogen, USA) in the assay is 100 nM. Kinase reactions were initiated with the addition of 100 nM ATP in the presence of serials of dilutions of compounds. The reactions were allowed to proceed for 1 h at room temperature before a 10 uL preparation of EDTA (20 mM) and Eu-labeled antibody (4 nM) in TR-FRET dilution buffer are added. The final concentration of antibody in the assay well is 2 nM, and the final concentration of EDTA is 10 mM. The plate is allowed to incubate at room temperature for one more hour before the TR-FRET emission ratios of 665 nm/340 nm were acquired on a PerkinElmer EnVision multilabel reader (Perkin-Elmer, Inc.). Data analysis and curve fitting were performed using GraphPad Prism4 software, resulting in the half maximal inhibitory concentration (IC50) shown in table 1. The functional assays of compounds on the kinase activities of c-kit and Abl were determined using the FRET-based Z'-Lyte assay system according to the manufacturer's instructions (Invitrogen, USA). Tyrosine 2 peptide was used as Abl substrate, and Ser/Thr 6 peptide was used as the substrate for c-kit. The reactions were carried out in 384-well plates in a 10 uL of reaction volume with appropriate amount of kinases in 50 mM HEPES (pH 7.5), 10 Mm MgCl2, 1 mM EGTA, and 0.01% Brij-35. The reactions were incubated 1 h at room temperature in the presence of 2 uM of substrate with 10 uM of ATP (for Abl1 assays) or 300 uM of ATP (kit assay) and in the presence of various concentrations of the compounds.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 510.56, ALogP 4.06, HBA 6, HBD 1, PSA 64.6, QED 0.56
Compound (SMILES): Cc1cnc(-c2cc(OCC3CCOCC3)cc(C(=O)NC(C)c3ncc(F)cc3Cl)c2)s1
InChIKey: YAVBCOZWMZVERS-UHFFFAOYSA-N
Target: P2X2/P2X3 heterotrimeric receptor (PROTEIN COMPLEX), Homo sapiens
UniProt: P56373
Assay: Intracellular Calcium Measurement to Assess Antagonist Activity : A fluorescent imaging plate reader (FLEX/FLIPR station; Molecular Devices) was used to monitor intracellular calcium levels using the calcium-chelating dye Fluo-4 (Molecular Probes). The excitation and emission wavelengths used to monitor fluorescence were 470-495 nm and 515-575 nm, respectively. Cells expressing purinergic receptors P2X3 (human) or P2X2/3 (human) were plated at a density of 15,000 cells/well in collagen-coated 384-well plates approximately 20 hours before beginning the assay. On the day of the assay, 20 μl of loading buffer (Hank's balanced salt solution, 20 mM HEPES, 0.5 mM CaCl2, 0.5 mM MgCl2, 0.1% BSA, 5 mM probenecid, 10 mM D-glucose monohydrate, 2 μM Fluo-4, and 5 units/mL, hexokinase, pH=7.4) was added and cells dye-loaded for 90 min at 37° C. The dye supernatant was removed and replaced with 45 μl probenecid buffer (Hank's balanced salt solution, 20 mM HEPES, 0.5 mM CaCl2, 0.5 mM MgCl2, 0.1% BSA, 5 mM probenecid, 10 mM D-glucose monohydrate, pH=7.4). The test compound was added in a volume of 5 μl and allowed to incubate for 30 min at 37° C. The final assay DMSO concentration is 1%.The agonist, α,β-Me-ATP, was added in a volume of 20 μl at a concentration representing the EC80 value. The fluorescence was measured for an interval of 90 sec at 2 sec intervals and analyzed based on the increase in peak relative fluorescence units (RFU) compared to the basal fluorescence. Peak fluorescence was used to determine the response to agonist obtained at each concentration of test compound by the following equation: % Response=100*(RFU(test compound)−RFU(control))/(RFU(DMSO)−RFU(control)).
Measurement: IC50 = 1077 nM (pChEMBL 5.96999979019165)
Descriptors: MW 490, ALogP 5.6, HBA 6, HBD 1, PSA 73.34, QED 0.47
Compound (SMILES): CN1CCN(S(=O)(=O)c2ccc(Nc3ncc4cc5n(c4n3)C3(CCCCC3)C(=O)NC5O)cc2)CC1
InChIKey: CXMKIWPGGSLHRE-UHFFFAOYSA-N
Target: CDK6/cyclin D3 (PROTEIN COMPLEX), Homo sapiens
UniProt: Q00534
Assay: CDK Inhibition In Vitro Assay: Selected compounds disclosed herein were tested in kinase assays by Nanosyn (Santa Clara, Calif.) to determine their inhibitory effect on these CDKs. The assays were performed using microfluidic kinase detection technology (Caliper Assay Platform). The compounds were tested in 12-point dose-response format in singlicate at Km for ATP. Specifics of each assay are as described below:CDK1/Cyclin B1: Enzyme concentration: 0.08 nM; ATP concentration: 40 μM; Incubation time: 3 hr. CDK2/Cyclin A: Enzyme concentration: 0.1 nM; ATP concentration: 50 μM; Incubation time: 3 hr. CDK2/Cyclin E: Enzyme concentration: 0.15 nM; ATP concentration: 100 μM; Incubation time: 3 hr. CDK4/Cyclin D1: Enzyme concentration: 1 nM; ATP concentration: 200 μM; Incubation time: 3 hr. CDK6/Cyclin D3: Enzyme concentration: 2 nM; ATP concentration: 300 μM; Incubation time: 3 hr. CDK9/Cyclin T1: Enzyme concentration: 5 nM; ATP concentration: 10 μM; Incubation time: 17 hr.
Measurement: IC50 = 51 nM (pChEMBL 7.289999961853027)
Descriptors: MW 525.64, ALogP 1.89, HBA 9, HBD 3, PSA 132.69, QED 0.47
Compound (SMILES): CN1CCN(S(=O)(=O)c2ccc(Nc3ncc4cc5n(c4n3)C3(CCCCC3)C(=O)NC5O)cc2)CC1
InChIKey: CXMKIWPGGSLHRE-UHFFFAOYSA-N
Target: CDK9/cyclin T1 (PROTEIN COMPLEX), Homo sapiens
UniProt: O60563
Assay: CDK Inhibition In Vitro Assay: Selected compounds disclosed herein were tested in kinase assays by Nanosyn (Santa Clara, Calif.) to determine their inhibitory effect on these CDKs. The assays were performed using microfluidic kinase detection technology (Caliper Assay Platform). The compounds were tested in 12-point dose-response format in singlicate at Km for ATP. Specifics of each assay are as described below:CDK1/Cyclin B1: Enzyme concentration: 0.08 nM; ATP concentration: 40 μM; Incubation time: 3 hr. CDK2/Cyclin A: Enzyme concentration: 0.1 nM; ATP concentration: 50 μM; Incubation time: 3 hr. CDK2/Cyclin E: Enzyme concentration: 0.15 nM; ATP concentration: 100 μM; Incubation time: 3 hr. CDK4/Cyclin D1: Enzyme concentration: 1 nM; ATP concentration: 200 μM; Incubation time: 3 hr. CDK6/Cyclin D3: Enzyme concentration: 2 nM; ATP concentration: 300 μM; Incubation time: 3 hr. CDK9/Cyclin T1: Enzyme concentration: 5 nM; ATP concentration: 10 μM; Incubation time: 17 hr.
Measurement: IC50 = 2 nM (pChEMBL 8.699999809265137)
Descriptors: MW 525.64, ALogP 1.89, HBA 9, HBD 3, PSA 132.69, QED 0.47
Compound (SMILES): CS(=O)(=O)Nc1ccc(-c2ncc(C(=O)NCc3cn(-c4cc(Cl)ccn4)nn3)s2)cc1
InChIKey: DCPVLHWWHLOPSX-UHFFFAOYSA-N
Target: P2X purinoceptor 7 (SINGLE PROTEIN), Homo sapiens
UniProt: Q99572
Assay: Antagonist activity at human P2X7 receptor expressed in HEK293 cells assessed as inhibition of ATP-induced receptor pore formation by propidium iodide dye uptake based fluorescence analysis
Measurement: IC50 = 340 nM (pChEMBL 6.46999979019165)
Descriptors: MW 489.97, ALogP 2.74, HBA 9, HBD 2, PSA 131.76, QED 0.41
Compound (SMILES): Fc1ccc(Nc2c3c(nc4cc(Cl)ccc24)CCCC3)cc1Cl
InChIKey: NOLHCVSBSMPRCH-UHFFFAOYSA-N
Target: Son of sevenless homolog 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q07889
Assay: Agonist activity at SOS1 in human HeLa cells assessed as activation of p-ERK1/2 incubated for 30 mins by immunoblot analysis
Measurement: EC50 = 3700 nM (pChEMBL 5.429999828338623)
Descriptors: MW 361.25, ALogP 6.3, HBA 2, HBD 1, PSA 24.92, QED 0.58
Compound (SMILES): CC[C@@H](CN1CCN(S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1)Nc1ncnc2c(C)csc12
InChIKey: VKRNKJOWCXWQFT-HNNXBMFYSA-N
Target: Lysophosphatidic acid receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9HBW0
Assay: Antagonist activity at human LPA2 receptor expressed in CHO cells assessed as inhibition of LPA-induced calcium mobilization pretreated for 15 mins followed by LPA stimulation by FLIPR analysis
Measurement: IC50 = 6165.95 nM (pChEMBL 5.210000038146973)
Descriptors: MW 514.5, ALogP 4.5, HBA 7, HBD 1, PSA 78.43, QED 0.5
Compound (SMILES): Cc1nc2ccc(-c3ccc(NC(=O)NCCN(C)C)cc3)cc2n1-c1cccc(NS(=O)(=O)C2CC2)c1
InChIKey: GBTREBAWHSFAIF-UHFFFAOYSA-N
Target: Serine-protein kinase ATM (SINGLE PROTEIN), Homo sapiens
UniProt: Q13315
Assay: Inhibition of human ATM kinase using p53 as substrate by FRET assay
Measurement: IC50 = 8 nM (pChEMBL 8.100000381469727)
Descriptors: MW 532.67, ALogP 4.59, HBA 6, HBD 3, PSA 108.36, QED 0.29
Compound (SMILES): CO[C@H]1CC[C@H](NC(=O)c2cncc(-c3ccncc3)n2)CC1
InChIKey: IGMSQPGPTPFNHS-HDJSIYSDSA-N
Target: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P28907
Assay: Inhibition of human CD38 using epslon-NAD as substrate and measured for 1 hrs by fluorescence based microplate reader analysis
Measurement: IC50 > 1000 nM (pChEMBL 6)
Descriptors: MW 312.37, ALogP 2.23, HBA 5, HBD 1, PSA 77, QED 0.94
Compound (SMILES): O=C(NCCCCN1CCN(c2ccccc2F)CC1)c1n[nH]c2ccccc12
InChIKey: YLGXHKHIKDCOIA-UHFFFAOYSA-N
Target: D(2) dopamine receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P14416
Assay: Displacement of [3H]-spiperone from human D2s receptor expressed in CHO-K1 cells membrane incubated for 1 hr by microbeta liquid scintillation counting analysis
Measurement: Ki = 26.4 nM (pChEMBL 7.579999923706055)
Descriptors: MW 395.48, ALogP 3.03, HBA 4, HBD 2, PSA 64.26, QED 0.6
Compound (SMILES): CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CO)O[C@@H](Sc2ccc(S(N)(=O)=O)cc2)[C@@H]1OC(C)=O
InChIKey: GEPXKKLRMYWXND-ICUGJSFKSA-N
Target: Carbonic anhydrase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P00915
Assay: Binding affinity to human recombinant carbonic anhydrase 1 assessed as inhibition constant incubated for 15 mins by phenol red based stopped-flow CO2 hydration assay
Measurement: Ki = 84.4 nM (pChEMBL 7.070000171661377)
Descriptors: MW 477.51, ALogP -0.06, HBA 11, HBD 2, PSA 168.52, QED 0.4
Compound (SMILES): Cc1nnc2n1-c1ccc(-c3cnn(CC(=O)NCCCCCC#Cc4cccc5c4CN(C4CCC(=O)NC4=O)C5=O)c3)cc1C(Nc1ccc(Cl)cc1)CC2
InChIKey: QPJCVFSNZRSPGP-UHFFFAOYSA-N
Target: Bromodomain-containing protein 3 (SINGLE PROTEIN), Homo sapiens
UniProt: Q15059
Assay: Binding affinity to recombinant human BRD3 BD1 (24 to 144 residues) assessed as inhibition constant by fluorescence polarization binding assay
Measurement: Ki = 32.88 nM (pChEMBL 7.480000019073486)
Descriptors: MW 784.32, ALogP 5.68, HBA 10, HBD 3, PSA 156.14, QED 0.09
Compound (SMILES): c1ccc2c(NC3CCCCC3)nc(C3CC3)nc2c1
InChIKey: ZQMGQZOHIDOPCQ-UHFFFAOYSA-N
Target: N-glycosylase/DNA lyase (SINGLE PROTEIN), Homo sapiens
UniProt: O15527
Assay: Activation of OGG1 (unknown origin) by fluorescence-based assay
Measurement: EC50 = 780 nM (pChEMBL 6.110000133514404)
Descriptors: MW 267.38, ALogP 4.25, HBA 3, HBD 1, PSA 37.81, QED 0.9
Compound (SMILES): COc1cc2c(cc1Nc1nc(Nc3ccccc3S(=O)(=O)N(C)C)c3cc[nH]c3n1)CN(C)CC2
InChIKey: WVKSLTSWAADBFD-UHFFFAOYSA-N
Target: Mitogen-activated protein kinase kinase kinase kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q92918
Assay: Inhibition of human HPK1 using myelin basic protein and [gamma33P]ATP as substrate incubated for 40 mins in presence of Mg/ATP by radiometric scintillation counting analysis
Measurement: IC50 = 2.5 nM (pChEMBL 8.600000381469727)
Descriptors: MW 507.62, ALogP 3.69, HBA 8, HBD 3, PSA 115.48, QED 0.35
Compound (SMILES): CC1Cc2ccccc2N1C(=O)c1cc(Cl)c(O)c(Cl)c1
InChIKey: DXWTVERSFABTAS-UHFFFAOYSA-N
Target: Solute carrier family 22 member 12 (SINGLE PROTEIN), Homo sapiens
UniProt: Q96S37
Assay: Inhibition of human URAT1 stably overexpressing in human HEK293 cells assessed as inhibition of 14C-uric acid uptake preincubated for 30 mins followed by substrate addition and measured after 15 mins using 14C-uric acid as substrate by liquid scintillation counting analysis
Measurement: IC50 = 1600 nM (pChEMBL 5.800000190734863)
Descriptors: MW 322.19, ALogP 4.29, HBA 2, HBD 1, PSA 40.54, QED 0.85
Compound (SMILES): CCn1c(=O)ccn(Cc2cnc(-c3ccc(F)c(O)c3F)s2)c1=O
InChIKey: ACWSXEQLWLKUFN-UHFFFAOYSA-N
Target: 17-beta-hydroxysteroid dehydrogenase 13 (SINGLE PROTEIN), Homo sapiens
UniProt: Q7Z5P4
Assay: Inhibition of recombinant human full-length C-terminal His-tagged HSD17B13 using estradiol and NAD as substrate preincubated for 10 mins followed by substrate addition and measured after 40 mins by MALDI-TOF-MS analysis
Measurement: IC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 365.36, ALogP 2.19, HBA 7, HBD 1, PSA 77.12, QED 0.77
Compound (SMILES): CC[C@H](C)[C@@H]1NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]2CSSC[C@H](NC(=O)CNC(=O)[C@@H](N)CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)O)NC1=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N2
InChIKey: KFARFZQXOCJFKM-RFAHKMTNSA-N
Target: Neuronal acetylcholine receptor subunit alpha-7 (SINGLE PROTEIN), Homo sapiens
UniProt: P36544
Assay: Antagonist activity at alpha7 nAChRs in human SH-SY5Y cells assessed as increase in intracellular calcium level by FLIPR assay
Measurement: IC50 > 10 nM (pChEMBL 8)
Descriptors: MW 1747.99
Compound (SMILES): O=C(Nc1cccc2ncn(Cc3ccn(-c4ccccc4)n3)c(=O)c12)c1cc(Cl)c(O)c(Cl)c1
InChIKey: PEZFJHJVVLOUKZ-UHFFFAOYSA-N
Target: 17-beta-hydroxysteroid dehydrogenase 13 (SINGLE PROTEIN), Homo sapiens
UniProt: Q7Z5P4
Assay: Inhibition of His-tagged HSD17B13 (unknown origin) expressed in Escherichia coli using estradiol as substrate incubated for 2 hrs and measured by LC/MS estrone detection assay
Measurement: IC50 = 100 nM (pChEMBL 7)
Descriptors: MW 506.35, ALogP 4.9, HBA 7, HBD 2, PSA 102.04, QED 0.35
Compound (SMILES): Cc1cccc(C(=O)N2Cc3c[nH]c(=O)c4c(C)cc(n34)-c3cc(CS(C)(=O)=O)ccc32)c1C
InChIKey: RBZSRTKUOKJCLI-UHFFFAOYSA-N
Target: Bromodomain-containing protein 4 (SINGLE PROTEIN), Homo sapiens
UniProt: O60885
Assay: Inhibition of human N-terminal 6His-tagged BRD4 BD2 (351 to 457 residues) expressed in Escherichia coli BL21-CodonPlus (DE3) cells using biotinylated H4 peptide as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by AlphaScreen assay
Measurement: IC50 = 6.4 nM (pChEMBL 8.1899995803833)
Descriptors: MW 475.57, ALogP 3.92, HBA 5, HBD 1, PSA 91.72, QED 0.49
Compound (SMILES): O=C(O)Cc1c(C(=O)N2CCC(Oc3ccc(C(F)(F)F)cc3)CC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
InChIKey: YHAQIDILYSLWMW-UHFFFAOYSA-N
Target: Cannabinoid receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P21554
Assay: Inverse agonist activity at human CB1 receptor expressed in African green monkey COS7 cells co-expressing G-protein in presence of CP55940 by IP3 assay
Measurement: IC50 = 7 nM (pChEMBL 8.149999618530273)
Descriptors: MW 618.44, ALogP 7.18, HBA 5, HBD 1, PSA 84.66, QED 0.24
Compound (SMILES): Cc1ccc(NC(=O)c2ccc(CN3CCN(c4nnc(NC(=O)Cc5ccccc5)s4)CC3)cc2)cc1
InChIKey: KJGKQWNEMNIBOI-UHFFFAOYSA-N
Target: Glutaminase kidney isoform, mitochondrial (SINGLE PROTEIN), Homo sapiens
UniProt: O94925
Assay: Inhibition of GLS1 (unknown origin)
Measurement: IC50 = 212 nM (pChEMBL 6.670000076293945)
Descriptors: MW 526.67, ALogP 4.6, HBA 7, HBD 2, PSA 90.46, QED 0.35
Compound (SMILES): CN1CC[C@@](O)(c2cc(-c3cccc(-c4cc(N5CC(F)(F)C5)cc(C(N)=O)n4)c3)no2)C1=O
InChIKey: PBVSWWLQRSIACR-HSZRJFAPSA-N
Target: Mitogen-activated protein kinase kinase kinase 14 (SINGLE PROTEIN), Homo sapiens
UniProt: Q99558
Assay: Inhibition of auto-phosphorylation of human GST-tagged NIK/MAP3K14 measured for 2 hrs by AlphaScreen assay
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 469.45, ALogP 2.01, HBA 7, HBD 2, PSA 125.79, QED 0.59
Compound (SMILES): Cc1ccc(-n2cc3c(N4CCCC(C(=O)NCc5ccc6sccc6c5)CC4)ncnc3n2)cc1F
InChIKey: NXKMBZJCLDIZNY-UHFFFAOYSA-N
Target: Nicotinamide phosphoribosyltransferase (SINGLE PROTEIN), Homo sapiens
UniProt: P43490
Assay: Positive allosteric modulation of C-terminal His6-tagged wild type human NAMPT using NAM and PRPP as substrates measured for 1 hr by NMNAT1-coupled enzyme assay
Measurement: EC50 = 25 nM (pChEMBL 7.599999904632568)
Descriptors: MW 514.63, ALogP 5.4, HBA 7, HBD 1, PSA 75.94, QED 0.34
Compound (SMILES): O=C(CN1C(=O)S/C(=C\c2ccc(O)cc2)C1=O)Nc1ccccc1O
InChIKey: LKPIUUSRFMCEMK-DHDCSXOGSA-N
Target: Aldo-keto reductase family 1 member B1 (SINGLE PROTEIN), Homo sapiens
UniProt: P15121
Assay: Inhibition of ALR2 (unknown origin)
Measurement: IC50 = 950 nM (pChEMBL 6.019999980926514)
Descriptors: MW 370.39, ALogP 2.77, HBA 6, HBD 3, PSA 106.94, QED 0.56
Compound (SMILES): COC(=O)c1cccc(Oc2cc(N)cc(NC(=O)c3cn(-c4ccccc4)nc3-c3ccccc3)c2)c1
InChIKey: ZHNQLGVWULLMSA-UHFFFAOYSA-N
Target: Estrogen-related receptor gamma (SINGLE PROTEIN), Mus musculus
UniProt: P62509
Assay: Inverse agonist activity at Gal4-tagged mouse ERR-gamma LBD transfected in HEK293T cells co-expressing FR-luc assessed as inhibition of transcriptional activity incubated for 24 hrs by luciferase reporter gene assay
Measurement: IC50 = 8420 nM (pChEMBL 5.079999923706055)
Descriptors: MW 504.55, ALogP 5.95, HBA 7, HBD 2, PSA 108.47, QED 0.21
Compound (SMILES): O=C(COc1ccc(C2CCC(=O)NC2=O)cc1)NCCCCCCNC(=O)COc1ccc(N(CC(F)(F)F)S(=O)(=O)C2CC3OC2C(c2ccc(O)cc2)=C3c2ccc(O)cc2)cc1
InChIKey: SHARBMRRUALJFH-UHFFFAOYSA-N
Target: Estrogen receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P03372
Assay: Binding affinity to ERalpha (unknown origin) assessed as inhibition constant incubated for 2 hrs by fluorescence polarization assay
Measurement: Ki = 1130 nM (pChEMBL 5.949999809265137)
Descriptors: MW 934.99, ALogP 5.72, HBA 11, HBD 5, PSA 209.9, QED 0.05
Compound (SMILES): O=C(c1cn(Cc2ccc(F)cc2)c2ccc(Br)cc12)C(F)(F)F
InChIKey: PPSXTCJOGVULII-UHFFFAOYSA-N
Target: Indoleamine 2,3-dioxygenase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P14902
Assay: Inhibition of IDO1 in human BXPC-3 cells assessed as reduction in IFNgamma induced kynurenine level incubated for 48 hrs by LC-MS analysis
Measurement: IC50 = 770 nM (pChEMBL 6.110000133514404)
Descriptors: MW 400.17, ALogP 5.34, HBA 2, HBD 0, PSA 22, QED 0.43
Compound (SMILES): COc1ccn2cc(CNC(=O)c3cccc4[nH]ncc34)nc2c1
InChIKey: CIYNUAFYHDPTBI-UHFFFAOYSA-N
Target: N6-adenosine-methyltransferase catalytic subunit (SINGLE PROTEIN), Homo sapiens
UniProt: Q86U44
Assay: Inhibition of full length His-tagged METTL3 (unknown origin) co-expressed with full length FLAG-tagged METTL14 in baculovirus expression system preincubated using 5'P-uacacucgaucuggacuaaagcugcuc-3' as substrate and SAM as cosubstrate pre-incubated for 10 mins followed by addition of substrates and measured after 60 mins by RapidFire mass spectrometry (RF/MS) analysis
Measurement: IC50 = 2670 nM (pChEMBL 5.570000171661377)
Descriptors: MW 321.34, ALogP 2.15, HBA 5, HBD 2, PSA 84.31, QED 0.6
Compound (SMILES): Cc1ns/c(=N\C(=N\c2ccccc2)c2ccccc2)n1Cc1cccc(O)c1
InChIKey: GFLUHHUQEOZIBT-KUXGFVDGSA-N
Target: Cystic fibrosis transmembrane conductance regulator (SINGLE PROTEIN), Homo sapiens
UniProt: P13569
Assay: Corrector activity at CFTR F508del mutant in human CFBE41o- cells coexpressing HS-YFP incubated for 25 mins by microplate reader based analysis
Measurement: EC50 = 1600 nM (pChEMBL 5.800000190734863)
Descriptors: MW 400.51, ALogP 4.69, HBA 5, HBD 1, PSA 62.77, QED 0.4
Compound (SMILES): CC(=O)NCCc1cc(O)c(O)cc1[C@@H](NC(C)=O)C(=O)c1ccc(O)c(O)c1
InChIKey: LKOSYWKZQSRSLK-LJQANCHMSA-N
Target: Rho-associated protein kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13464
Assay: Inhibition of ROCK1 (unknown origin) incubated for 1 hr by FRET based Z'-lyte assay
Measurement: IC50 = 29100 nM (pChEMBL 4.539999961853027)
Descriptors: MW 402.4, ALogP 1.25, HBA 7, HBD 6, PSA 156.19, QED 0.3
Compound (SMILES): O=c1ccccn1-c1ccc(N[C@H]2CC[C@H](Nc3ncc(C4CC4)cn3)C2)nc1
InChIKey: WSEPMXYCJDITKB-ROUUACIJSA-N
Target: Proprotein convertase subtilisin/kexin type 9 (SINGLE PROTEIN), Homo sapiens
UniProt: Q8NBP7
Assay: Surface Plasmon Resonance (SPR) Assay: Surface plasmon resonance data was collected on a Biacore T200 or 3000 system (GE Healthcare) at 25° C. Streptavidin was immobilized on a CMS (GE Healthcare) or CMD500d sensor chip (XanTec Bioanalytics) using standard amine-coupling chemistry at 25° C. with HBS-N (10 mM HEPES, 0.15 M NaCl, pH 7.4) as the running buffer. Briefly, the carboxymethyl dextran surface was activated with a 12 min injection of a 1:1 ratio of 0.4 M 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/0.1 M N-hydroxy succinimide (NHS) at a flow rate of 10 μL/min. For capture of streptavidin, protein was diluted to 0.2 mg/mL in 10 mM sodium acetate (pH 4.5) and captured by injecting 100 μL onto the activated chip surface. Residual activated groups were blocked with a 7 min injection of 1 M ethanolamine (pH 8.5). Avi-tagged PCSK9 protein was captured on the streptavidin surface by injection of 150 μL of protein diluted to 16 μg/mL in HBS-N, 0.05% tween-20, 0.1 mM CaCl2. Typical surface densities obtained were 8000-10000 RU. SPR binding data were obtained using an appropriate dilution series of each compound at a flow rate of 30 μL/ min, with a capture time of 100 s and dissociation times of 300 s. Running buffer for compound binding studies was HBS-N, 0.05% tween-20, 0.1 mM CaCl2, 4% DMSO. Data were corrected for DMSO excluded volume effects. All data were double-referenced for blank injections and reference surface using standard processing procedures and data processing and kinetic fitting were performed using Scrubber software, version 2.0c (BioLogic Software).
Measurement: Kd < 200 nM (pChEMBL 6.698999881744385)
Descriptors: MW 388.48, ALogP 3.35, HBA 7, HBD 2, PSA 84.73, QED 0.67
Compound (SMILES): CCC(=O)N1CCCN(C(=O)C2CCCN(C(=O)c3ccc(NC(=O)N[C@@]45C[C@@H]6C[C@@](C)(C[C@@](C)(C6)C4)C5)c(F)c3)C2)CC1
InChIKey: MDDFSGQTCDBGNI-OCKHGLHXSA-N
Target: Bifunctional epoxide hydrolase 2 (SINGLE PROTEIN), Mus musculus
UniProt: P34914
Assay: Inhibition of recombinant mouse soluble epoxide hydrolase using PHOME as substrate assessed as 6-methoxynaphthaldehyde product formation preincubated with compound for 10 mins followed by substrate addition and measured by fluorescence based analysis
Measurement: IC50 = 0.58 nM (pChEMBL 9.239999771118164)
Descriptors: MW 609.79, ALogP 5.02, HBA 4, HBD 2, PSA 102.06, QED 0.49
Compound (SMILES): Cc1cc(Nc2nccc(N(C)c3ccc4c(C)n(C)nc4c3)n2)cnc1-c1nc2c(C(N)=O)cccc2[nH]1
InChIKey: CSGHPSLYQBFKEY-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Inhibition of VEGFR2 (unknown origin) by Z'-Lyte kinase assay
Measurement: IC50 = 235 nM (pChEMBL 6.630000114440918)
Descriptors: MW 518.59, ALogP 4.53, HBA 9, HBD 3, PSA 143.53, QED 0.29
Compound (SMILES): CCn1cc2cc(C(=O)Nc3ccc4[nH]c(CN5CCC[C@@H]5C)nc4c3)ccc2n1
InChIKey: ACXBMPHDZJWALT-HNNXBMFYSA-N
Target: Protein ENL (SINGLE PROTEIN), Homo sapiens
UniProt: Q03111
Assay: Inhibition of C-terminal 6xHis-tagged ENL YEATS domain (1 to 148 residues) (unknown origin) expressed in Escherichia coli BL21(DE3) cells using biotin-H3K27ace as substrate incubated for 45 mins by alpha screen assay
Measurement: IC50 = 36.7 nM (pChEMBL 7.429999828338623)
Descriptors: MW 402.5, ALogP 4.17, HBA 5, HBD 2, PSA 78.84, QED 0.53
Compound (SMILES): CCCCCCCCOP(=O)([O-])OC1=Cc2ccccc2Sc2c(OC)cccc21.[Na+]
InChIKey: JYCVZRVUTWNXTR-UHFFFAOYSA-M
Target: G-protein coupled receptor 84 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NQS5
Assay: Antagonist activity at human GPR84 expressed in HEK293 cells co-expressing Galpha16 assessed as inhibition of 6-OAU induced calcium response incubated for 10 mins by calcium mobilization assay
Measurement: IC50 = 108 nM (pChEMBL 6.96999979019165)
Descriptors: MW 448.52, ALogP 7.15, HBA 5, HBD 1, PSA 64.99, QED 0.29
Compound (SMILES): COc1ccccc1OCCn1cc(C(=O)C(F)(F)F)c2cc(Br)ccc21
InChIKey: FEGWGVYSFIPVAX-UHFFFAOYSA-N
Target: Indoleamine 2,3-dioxygenase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P14902
Assay: Inhibition of IDO1 in human BXPC-3 cells assessed as reduction in IFNgamma induced kynurenine level incubated for 48 hrs by LC-MS analysis
Measurement: IC50 = 5430 nM (pChEMBL 5.260000228881836)
Descriptors: MW 442.23, ALogP 5.24, HBA 4, HBD 0, PSA 40.46, QED 0.49
Compound (SMILES): FC(F)c1nnc(-c2ccc(Cn3nnc(-c4ccccn4)n3)cn2)o1
InChIKey: LLZKMLBXVXOQIQ-UHFFFAOYSA-N
Target: Protein deacetylase HDAC6 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9UBN7
Assay: Inhibition of full length TEV-cleavable N-terminal His6-tagged human recombinant HDAC6 using Ac-RGK (Ac)-AMC as substrate preincubated for 20 hrs followed by substrate addition and measured after 3 hrs by microplate reader analysis
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 356.3, ALogP 2.17, HBA 9, HBD 0, PSA 108.3, QED 0.54
Compound (SMILES): N#Cc1ccc(COc2nc(N3CCC4(CC3)C[C@@H]4c3nc4ccc(C(=O)O)cc4n3C[C@@H]3CCO3)ccc2F)c(F)c1
InChIKey: LRSGIYCSDGYUAQ-XZOQPEGZSA-N
Target: Glucagon-like peptide 1 receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P43220
Assay: Displacement of [125I]-GLP1 from GLP-1 receptor (unknown origin) expressed in CHO cells membrane pre-incubated for 10 mins followed by [125I]-GLP1 addition and measured after 180 mins by microbeta scintillation counting method
Measurement: EC50 = 14 nM (pChEMBL 7.849999904632568)
Descriptors: MW 585.61, ALogP 5.42, HBA 8, HBD 1, PSA 113.5, QED 0.29
Compound (SMILES): O=C(O)c1cc2cc(NC(=O)[C@@H]3CCc4cc(-c5cc(Cl)ccc5-n5cnnn5)cc(=O)n43)ccc2[nH]1
InChIKey: WZZLEVNLUGKSFY-QFIPXVFZSA-N
Target: Coagulation factor XI (SINGLE PROTEIN), Homo sapiens
UniProt: P03951
Assay: Inhibition of FXIa (unknown origin)
Measurement: IC50 = 6.4 nM (pChEMBL 8.1899995803833)
Descriptors: MW 515.92, ALogP 3.45, HBA 8, HBD 3, PSA 147.79, QED 0.32