lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): COC1CN(C(=O)CN2CCC(c3cc4c(-c5cc(F)ccc5O)ccnc4[nH]3)CC2)C1
InChIKey: IMVGISYMFJDMNT-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 = 39 nM (pChEMBL 7.409999847412109)
Descriptors: MW 438.5, ALogP 3.11, HBA 5, HBD 2, PSA 81.69, QED 0.64
Compound (SMILES): Cc1c(-c2nc(Nc3ccc(N4CCN(C)CC4)cn3)ncc2F)sc2c1nc(C)n2C(C)C
InChIKey: WBYYUUNGKPRTDJ-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 480.62, ALogP 4.78, HBA 9, HBD 1, PSA 75, QED 0.44
Compound (SMILES): CC(=O)N[C@@H]1CCC[C@H](C(=O)Nc2cc(-c3ccc4nsc(C(C)C)c4c3)c(Cl)cn2)C1
InChIKey: NJJPIXGNLMGEOV-DLBZAZTESA-N
Target: CDK2/Cyclin A2 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24941
Assay: CDK9/CyclinT1 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). CDK9/Cyclin T1 catalyzed phosphorylation of peptide in the presence and absence of compounds was measured and used in IC50 determination. Recombinant protein complex CDK9/Cyclin T1, 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 CDK9/CyclinT1 (1 nM final), ULight-4E-BP1 (50 nM final, Perkinelmer, TRF0128-D), and ATP (1 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). IC50values were determined by fitting the data to the standard 4 parameters with Hill Slope using GraphPad Prism software. See Table B (CDK9_T1).
Measurement: IC50 = 129 nM (pChEMBL 6.889999866485596)
Descriptors: MW 471.03, ALogP 5.77, HBA 5, HBD 2, PSA 83.98, QED 0.5
Compound (SMILES): COc1cc(Cl)ccc1S(=O)(=O)N[C@H](c1n[nH]c(=O)o1)[C@H](C)c1cccc2cccc(C)c12
InChIKey: IRMGRKYAWRQXGM-SZNDQCEHSA-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 = 240 nM (pChEMBL 6.619999885559082)
Descriptors: MW 487.97, ALogP 4.31, HBA 6, HBD 2, PSA 114.29, QED 0.4
Compound (SMILES): CC(C)C1CNC(=O)c2cc3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n21
InChIKey: JKNBNAZZNVQNBP-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 2/cyclin E1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24941
Assay: Kinase Enzymatic Assay: Kinase enzymatic reactions were performed in 384-well microplates using a 12-channel Caliper LabChip instrument as a detection device. The enzymatic phosphorylation of a peptide results in a change in net charge, enabling electrophoretic separation of product from substrate. As substrate and product are separated, two peaks of fluorescence are observed. Change in the relative fluorescence intensity of the substrate and product peaks is the parameter measured, reflecting enzyme activity. In the presence of an inhibitor, the ratio between product and substrate is altered. The signal of the product decreases, while the signal of the substrate increases.For the measurement of CDK2/cyclinE activity, enzyme (0.22 nM) was incubated with 100 mM ATP and the phosphoacceptor substrate peptide (1 mM) for one hour. For the measurement of CDK4/CyclinD activity, enzyme (0.85 nM) was incubated with 200 mM ATP and the phosphoacceptor substrate peptide (1 mM) for three hours. Potential inhibitor compounds (as HCl salts) were tested using 12-point dose response curves in single point at the Km for ATP.
Measurement: IC50 = 50500 nM (pChEMBL 4.300000190734863)
Descriptors: MW 406.49, ALogP 1.92, HBA 8, HBD 3, PSA 100, QED 0.61
Compound (SMILES): CC(F)(F)c1cc(-c2cncc(CN3CC(C(=O)N4CCC4)OC3=O)n2)ccc1F
InChIKey: SBYYLOMCHANCFL-UHFFFAOYSA-N
Target: Glutamate NMDA receptor; GRIN1/GRIN2B (PROTEIN COMPLEX), Homo sapiens
UniProt: Q13224
Assay: Effect of Compounds of Formula (I) on Cloned Human GluN1/GluN2B Ion Channels Expressed in Mammalian Cells: 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 (standard assay) or 1.5 mM MgCl2 (HTS assay), 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 (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 EC40 (standard assay) or EC40 (HTS assay) is 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 > 3000 nM (pChEMBL 5.5229997634887695)
Descriptors: MW 420.39, ALogP 2.95, HBA 5, HBD 0, PSA 75.63, QED 0.74
Compound (SMILES): COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(C4C[C@@H](C(=O)O)N(S(C)(=O)=O)C4)CC3)cc12
InChIKey: MJMXSVXOLMVBMM-UGNFMNBCSA-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 = 91 nM (pChEMBL 7.039999961853027)
Descriptors: MW 514.58, ALogP 2.95, HBA 6, HBD 2, PSA 115.83, QED 0.52
Compound (SMILES): CC(C#N)Oc1ccc(-n2cnc(-c3nc(NC4CCN(S(C)(=O)=O)CC4)ncc3C(F)(F)F)c2)c(C(F)(F)F)n1
InChIKey: JVJJSLRMPZHIAM-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 604.54, ALogP 3.89, HBA 10, HBD 1, PSA 138.92, QED 0.4
Compound (SMILES): CC(C)NC(=O)O[C@@H]1CC[C@H](c2cc(NC(=O)Cc3ccn(C)n3)n[nH]2)C1
InChIKey: ONKRKQQVPIGVFI-GXTWGEPZSA-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 = 3.02 nM (pChEMBL 8.520000457763672)
Descriptors: MW 374.45, ALogP 2.1, HBA 6, HBD 3, PSA 113.93, QED 0.72
Compound (SMILES): CN1CCN(CCCS(=O)(=O)N2CC[C@H](Nc3ncc(C(F)(F)F)c(-c4cnn(CC(C)(C)O)c4)n3)[C@H](F)C2)CC1=O
InChIKey: QJGUSDZMGUVPGI-UXHICEINSA-N
Target: Cyclin-dependent kinase 2/cyclin E1 (PROTEIN COMPLEX), Homo sapiens
UniProt: P24941
Assay: CDK2/Cyclin E1 HERE 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 (Cama Product Number 04-165). Assays are conducted in white 384-well polystyrene plates in a final reaction volume of 8 μL. CDK2/Cyclin E1 (0.25 nM) is incubated with compounds (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 are 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 are read after 1 hour at room temperature on a PHERAstar FS plate reader (BMG Labtech). Data is 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 620.67, ALogP 1.45, HBA 10, HBD 2, PSA 136.79, QED 0.38
Compound (SMILES): Cc1cc(-c2cnc3cnn(Cc4cccnc4C)c3c2)ccc1F
InChIKey: MGWGAICTJJYKDY-UHFFFAOYSA-N
Target: Glutamate NMDA receptor; GRIN1/GRIN2B (PROTEIN COMPLEX), Homo sapiens
UniProt: Q13224
Assay: Effects of Test Articles on Cloned Human NR1/GuN2B Ion Channels Expressed in Mammalian Cells: 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 (standard assay) or 1.5 mM MgCl2 (HTS assay), 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 (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 EC40 (standard assay) or EC40 (HTS assay) is 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 = 507 nM (pChEMBL 6.289999961853027)
Descriptors: MW 332.38, ALogP 4.3, HBA 4, HBD 0, PSA 43.6, QED 0.56
Compound (SMILES): COc1ccc(F)cc1-c1ccnc2[nH]c(C3CC4CN(CC(O)CO)CC4C3)cc12
InChIKey: ZNYKFTOFGPEVLY-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 = 340 nM (pChEMBL 6.46999979019165)
Descriptors: MW 425.5, ALogP 3.16, HBA 5, HBD 3, PSA 81.61, QED 0.57
Compound (SMILES): COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCN(CC(=O)N4CCC[C@H]4CO)CC3)cc12
InChIKey: ZRXIWZFVJPAHQP-SFHVURJKSA-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 = 76 nM (pChEMBL 7.119999885559082)
Descriptors: MW 482.53, ALogP 3.59, HBA 5, HBD 2, PSA 81.69, QED 0.56
Compound (SMILES): COC1CN(Cc2ccc(-n3cnc(-c4nc(NC5CCN(S(C)(=O)=O)CC5)ncc4C(F)(F)F)c3)c(Cl)c2)C1
InChIKey: UTBMRUWNRXIFKX-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 600.07, ALogP 3.67, HBA 9, HBD 1, PSA 105.48, QED 0.42
Compound (SMILES): CCc1ccnc2cc(C(=O)NC[C@@H](N)C(=O)O)sc12
InChIKey: VWRBMYVRTNAYKU-MRVPVSSYSA-N
Target: Glutamate receptor ionotropic, NMDA 1/2C/3B (PROTEIN COMPLEX), Homo sapiens
UniProt: Q14957
Assay: Scintillation Proximity Assay: To determine the affinity of the compounds of the present invention a SPA is used. The assay is run in a 384-plate format (OptiPlate-384) where each well contains a mix of 5 μL of test compound, 5 μL NR1s1s2 (ligand binding domains of the NMDA receptor, MW 35.6 kDa, 0.075 ug/well final), 5 μL [3H]-MDL-105,519 (radiolabelled, high affinity N-methyl-D-aspartate (NMDA) glutamate receptor antagonist at the glycine site, final concentration 5 nM, Kd=1.3 nM), 5 μL streptavidin coated imaging beads (Perkin Elmer cat. No.: RPNQ0273, 8 ug/well). The assay buffer contains 100 mM HEPES-NaOH, 150 mM NaCl, 1 mM EDTA, 10% glycerol at pH 7.4 in ultra-pure water. Non-specific binding is defined by inclusion of 10 μM L-689,560 (highly potent NMDA antagonist) and total binding by 1% DMSO. Following 30 minutes incubation in the dark (shaker, Multi-microplate Genie), the SPA beads are allowed to settle for 3 hours after which the signal is read on a Viewlux instrument (Perkin Elmer). Normalized data are used to calculate Ki values.
Measurement: Ki = 270 nM (pChEMBL 6.570000171661377)
Descriptors: MW 293.35, ALogP 1, HBA 5, HBD 3, PSA 105.31, QED 0.76
Compound (SMILES): C=CC(=O)N1CCC(C(=O)Nc2cccc(CNc3nc(N[C@H]4CCC[C@@H](O)C4)nc4c(C(C)C)cnn34)c2)C1
InChIKey: MPRGZJIDIZHMNQ-XGELLPRESA-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 546.68, ALogP 3.55, HBA 9, HBD 4, PSA 136.78, QED 0.3
Compound (SMILES): CC(C)c1cnn2c(NCc3cccc(NC(=O)C4CCN(C(=O)/C=C/CN(C)C)C4)c3)nc(NC3CCOCC3)nc12
InChIKey: JDKUPKQKIILYPG-RMKNXTFCSA-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 < 300 nM (pChEMBL 6.5229997634887695)
Descriptors: MW 589.75, ALogP 3.36, HBA 10, HBD 3, PSA 129.02, QED 0.29
Compound (SMILES): CC(C(=O)Nc1cc(C2CCCC2)[nH]n1)c1cccc(-c2ccc(NC(=O)/C=C/CN(C)C)c(F)c2)c1
InChIKey: GUKWPWBWSGIXJS-KPKJPENVSA-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 503.62, ALogP 5.67, HBA 4, HBD 3, PSA 90.12, QED 0.33
Compound (SMILES): CCc1ccnc2cc(C(=O)NC[C@@H](N)C(=O)O)sc12
InChIKey: VWRBMYVRTNAYKU-MRVPVSSYSA-N
Target: Glutamate receptor ionotropic, NMDA 1/2C/3B (PROTEIN COMPLEX), Homo sapiens
UniProt: Q05586
Assay: Scintillation Proximity Assay: To determine the affinity of the compounds of the present invention a SPA is used. The assay is run in a 384-plate format (OptiPlate-384) where each well contains a mix of 5 μL of test compound, 5 μL NR1s1s2 (ligand binding domains of the NMDA receptor, MW 35.6 kDa, 0.075 ug/well final), 5 μL [3H]-MDL-105,519 (radiolabelled, high affinity N-methyl-D-aspartate (NMDA) glutamate receptor antagonist at the glycine site, final concentration 5 nM, Kd=1.3 nM), 5 μL streptavidin coated imaging beads (Perkin Elmer cat. No.: RPNQ0273, 8 ug/well). The assay buffer contains 100 mM HEPES-NaOH, 150 mM NaCl, 1 mM EDTA, 10% glycerol at pH 7.4 in ultra-pure water. Non-specific binding is defined by inclusion of 10 μM L-689,560 (highly potent NMDA antagonist) and total binding by 1% DMSO. Following 30 minutes incubation in the dark (shaker, Multi-microplate Genie), the SPA beads are allowed to settle for 3 hours after which the signal is read on a Viewlux instrument (Perkin Elmer). Normalized data are used to calculate Ki values.
Measurement: Ki = 270 nM (pChEMBL 6.570000171661377)
Descriptors: MW 293.35, ALogP 1, HBA 5, HBD 3, PSA 105.31, QED 0.76
Compound (SMILES): CN(c1ccc(Cl)cc1)c1ccnc(Nc2ccc(-c3nc4c(C(N)=O)cccc4[nH]3)cc2)n1
InChIKey: AUGRKZAFBVCEBZ-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 = 405 nM (pChEMBL 6.389999866485596)
Descriptors: MW 469.94, ALogP 5.28, HBA 6, HBD 3, PSA 112.82, QED 0.31
Compound (SMILES): Cn1ncc2c(Nc3ccc(F)cc3F)nc(NCC3(N)CC3)nc21
InChIKey: HIXYQPJNADWOII-UHFFFAOYSA-N
Target: RNA 5'-monophosphate methyltransferase (SINGLE PROTEIN), Homo sapiens
UniProt: Q7Z5W3
Assay: Inhibition of BCDIN3D (unknown origin) using mini-helix and SAM as substrate incubated for 1 hr by RapidFire High Throughput mass spectrometry
Measurement: IC50 = 1670 nM (pChEMBL 5.78000020980835)
Descriptors: MW 345.36, ALogP 2.29, HBA 7, HBD 3, PSA 93.68, QED 0.66
Compound (SMILES): CC1(N)CCN(c2ncc(C(=O)Nc3ccc4ccccc4c3)c(N)n2)CC1
InChIKey: LZYYQFBKGFDCGQ-UHFFFAOYSA-N
Target: Tyrosine-protein phosphatase non-receptor type 11 (SINGLE PROTEIN), Homo sapiens
UniProt: Q06124
Assay: Inhibition of pIRS-1 peptide activated human wild type SHP2 FL (Met1 to Leu525 residues) using DiFMUP as substrate preincubated for 30 mins followed by substrate addition and measured after 30 mins by microplate reader method
Measurement: IC50 = 8000 nM (pChEMBL 5.099999904632568)
Descriptors: MW 376.46, ALogP 2.78, HBA 6, HBD 3, PSA 110.16, QED 0.65
Compound (SMILES): COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccc(/C=C/C(=O)NO)cc3)CC1)C2
InChIKey: YDGCPLJSOWXJQC-BQYQJAHWSA-N
Target: Histone deacetylase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q13547
Assay: Inhibition of human HDAC1
Measurement: IC50 = 2430 nM (pChEMBL 5.610000133514404)
Descriptors: MW 464.56, ALogP 3.88, HBA 6, HBD 2, PSA 88.1, QED 0.35
Compound (SMILES): C[C@@H](CC(=O)NC[C@H](Cc1ccc(O)cc1)N(C)C)c1ccccc1
InChIKey: XDJWETHIUZQSGZ-LPHOPBHVSA-N
Target: Mu-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P35372
Assay: Agonist activity at human mu opioid receptor stably transfected in CHO cells by cAMP assay
Measurement: EC50 = 7.5 nM (pChEMBL 8.119999885559082)
Descriptors: MW 340.47, ALogP 3.17, HBA 3, HBD 2, PSA 52.57, QED 0.78
Compound (SMILES): CC(C)NC(=O)CSc1nc2nccnc2c(=O)n1CCc1ccccc1
InChIKey: SVQMYENHBBKPTL-UHFFFAOYSA-N
Target: Phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: O00443
Assay: Inhibition of PI3KC2alpha deltaN domain (unknown origin) preincubated for 5 mins followed by substrate addition and measured after 20 mins in the presence of 10 uM ATP by ADP-Glo reagent based Ultra-Glo luciferase assay
Measurement: IC50 > 50000 nM (pChEMBL 4.301000118255615)
Descriptors: MW 383.48, ALogP 2.05, HBA 7, HBD 1, PSA 89.77, QED 0.5
Compound (SMILES): CS(=O)(=O)Nc1ccc2[nH]c(C(=O)N3CCC(Nc4nccc(Oc5cccc(C#N)c5)n4)CC3)cc2c1
InChIKey: ZEEWFZPPEAQBOM-UHFFFAOYSA-N
Target: Human immunodeficiency virus type 1 reverse transcriptase (SINGLE PROTEIN), Human immunodeficiency virus 1
UniProt: Q72547
Assay: Inhibition of HIV-1 reverse transcriptase using [2,8-3H]dGTP as substrate by fluorescence based assay
Measurement: IC50 = 600 nM (pChEMBL 6.21999979019165)
Descriptors: MW 531.6, ALogP 3.71, HBA 8, HBD 3, PSA 153.1, QED 0.33
Compound (SMILES): COc1ccc(/C=C2\CCc3cc(O)ccc3C2=O)cc1
InChIKey: QCPZBJHECPIRCW-GXDHUFHOSA-N
Target: Macrophage migration inhibitory factor (SINGLE PROTEIN), Homo sapiens
UniProt: P14174
Assay: Inhibition of human recombinant MIF ketonase activity using phenylpyruvate as substrate
Measurement: IC50 = 67200 nM (pChEMBL 4.170000076293945)
Descriptors: MW 280.32, ALogP 3.61, HBA 3, HBD 1, PSA 46.53, QED 0.85
Compound (SMILES): O=c1[nH]cnc2cc(F)c(N3CCCC3)cc12
InChIKey: WCWHRVMPENINMJ-UHFFFAOYSA-N
Target: Inositol hexakisphosphate kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q92551
Assay: Inhibition of IP6K1 (unknown origin) incubated for 30 min in presence of ATP by ADPGlo reagent based assay
Measurement: IC50 = 12200 nM (pChEMBL 4.909999847412109)
Descriptors: MW 233.25, ALogP 1.66, HBA 3, HBD 1, PSA 48.99, QED 0.81
Compound (SMILES): Cc1ccc(-n2cc3c(N4CCC[C@H](C(=O)NCc5ccc(Br)cc5F)C4)ncnc3n2)cc1F
InChIKey: KQRVBLRRDUCNLQ-KRWDZBQOSA-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 = 460 nM (pChEMBL 6.340000152587891)
Descriptors: MW 541.4, ALogP 4.7, HBA 6, HBD 1, PSA 75.94, QED 0.4
Compound (SMILES): CCC(=O)N[C@@H]1CC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc2ccc(O)cc2)C(N)=O)CCCN/C(N)=N/C(=O)NCCCCNC1=O.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F
InChIKey: UDAUUIJOQIYHBS-JFCYTAHASA-N
Target: Neuropeptide Y receptor type 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P25929
Assay: Displacement of [3H]UR-MK299 from human Y1R expressed in SK-N-MC cells
Measurement: Ki > 1000 nM (pChEMBL 6)
Descriptors: MW 1192.39
Compound (SMILES): Cc1cc(-c2ccc(C#N)cc2)cc(Cl)c1Oc1nc(Nc2ccc(C#N)cc2)ncc1C(N)=O
InChIKey: FTEAHBFHACKLFH-UHFFFAOYSA-N
Target: Human immunodeficiency virus type 1 reverse transcriptase (SINGLE PROTEIN), Human immunodeficiency virus 1
UniProt: Q72547
Assay: Inhibition of recombinant wild type HIV-1 reverse transcriptase using DNA/RNA as substrate incubated for 40 mins by Pico-green dye based spectrofluorometric analysis
Measurement: IC50 = 66 nM (pChEMBL 7.179999828338623)
Descriptors: MW 480.92, ALogP 5.48, HBA 7, HBD 2, PSA 137.71, QED 0.37
Compound (SMILES): CC(C)C[C@H](N)CC(=O)NC1CCCc2c1[nH]c1ccc(F)cc21
InChIKey: GSTWZTPLYSSDIF-CWQZNGJJSA-N
Target: Bromodomain-containing protein 3 (SINGLE PROTEIN), Homo sapiens
UniProt: Q15059
Assay: Binding affinity to recombinant BRD3-ET domain (unknown origin) expressed in Escherichia coli Rosetta (DE3) pLysS assessed as dissociation constant by 1H- NMR analysis
Measurement: Kd = 39000 nM (pChEMBL 4.409999847412109)
Descriptors: MW 331.44, ALogP 3.56, HBA 2, HBD 3, PSA 70.91, QED 0.78
Compound (SMILES): Nc1ccc2cc(OCc3cn(CCOCCOc4ccc5ccc(N)nc5c4)nn3)ccc2n1
InChIKey: XJPMCAQROUNYOO-UHFFFAOYSA-N
Target: Neutrophil cytosol factor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P14598
Assay: Inhibition of Cy5-labeled p22phox (149 to 162 residues) probe binding to His-tagged human p47phox (151 to 286 residues) expressed in Escherichia coli BL21 (DE3) pLysS incubated for 10 to 15 mins by fluorescence polarization assay
Measurement: Ki = 6780 nM (pChEMBL 5.170000076293945)
Descriptors: MW 471.52, ALogP 3.21, HBA 10, HBD 2, PSA 136.22, QED 0.29
Compound (SMILES): CC(C)C[C@H](NC(=O)[C@@H]1CCCN/C(N)=N/C(=O)NCCCCNC(=O)[C@@H](N)CC(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](Cc1ccc(O)cc1)C(N)=O.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F.O=C(O)C(F)(F)F
InChIKey: JPOOIPCJAFXCKZ-HNBLRUEUSA-N
Target: Neuropeptide Y receptor type 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P25929
Assay: Displacement of [3H]UR-MK299 from human Y1R expressed in SK-N-MC cells
Measurement: Ki > 1000 nM (pChEMBL 6)
Descriptors: MW 1136.33
Compound (SMILES): COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(CNc3ccc(Cl)cc32)[C@H]1c1cccc(Cl)c1Cl
InChIKey: JFQUVXMAMAXJRE-LJQIRTBHSA-N
Target: E3 ubiquitin-protein ligase Mdm2 (SINGLE PROTEIN), Homo sapiens
UniProt: Q00987
Assay: Inhibition of MDM2 (1 to 118 residues)/p53 (unknown origin) interaction expressed in Escherichia coli BL21(DE3) cells assessed as inhibition constant incubated for 1.5 hrs by competitive fluorescence polarization assay
Measurement: Ki = 12.9 nM (pChEMBL 7.889999866485596)
Descriptors: MW 616.97, ALogP 7.22, HBA 5, HBD 4, PSA 99.69, QED 0.23
Compound (SMILES): Cn1nccc1-c1ccc2c(c1)CN([C@@H]1CNCC[C@H]1c1ccc(F)c(F)c1)C2=O
InChIKey: KPAACQKPTVIEFP-HTAPYJJXSA-N
Target: RAC-alpha serine/threonine-protein kinase (SINGLE PROTEIN), Homo sapiens
UniProt: P31749
Assay: Inhibition of AKT1 (unknown origin)
Measurement: IC50 = 4.3 nM (pChEMBL 8.369999885559082)
Descriptors: MW 408.45, ALogP 3.47, HBA 4, HBD 1, PSA 50.16, QED 0.72
Compound (SMILES): O=C1OCC2Cc3ccccc3N12
InChIKey: UYWJEDRSVUARIX-UHFFFAOYSA-N
Target: Palmitoleoyl-protein carboxylesterase NOTUM (SINGLE PROTEIN), Homo sapiens
UniProt: Q6P988
Assay: Inhibition of human recombinant Notum (81 to T451 residues) expressed in HEK293S cells using OPTS as substrate incubated for 40 mins by microplate reader analysis
Measurement: IC50 = 6100 nM (pChEMBL 5.210000038146973)
Descriptors: MW 175.19, ALogP 1.57, HBA 2, HBD 0, PSA 29.54, QED 0.6
Compound (SMILES): CCOC(=O)C1=CN(C(=O)c2cccc(OC)c2)C=C(C(=O)OCC)C1c1ccccc1
InChIKey: PQLABGPHTMLXQO-UHFFFAOYSA-N
Target: NAD-dependent protein deacetylase sirtuin-3, mitochondrial (SINGLE PROTEIN), Homo sapiens
UniProt: Q9NTG7
Assay: Binding affinity to N-terminal his-tagged human SIRT3 (114 to 380 residues) assessed as dissociation constant by SPR analysis
Measurement: Kd = 78000 nM (pChEMBL 4.110000133514404)
Descriptors: MW 435.48, ALogP 3.83, HBA 6, HBD 0, PSA 82.14, QED 0.62
Compound (SMILES): O/N=C/c1cc(Br)cc(CN2CCN(c3ccncc3)CC2)c1O
InChIKey: OPACGYUGWYNSQL-RGVLZGJSSA-N
Target: Acetylcholinesterase (SINGLE PROTEIN), Homo sapiens
UniProt: P22303
Assay: Binding affinity to DFP-inhibited human erythrocyte AChE assessed as dissociation constant preincubated with DFP for 15 mins followed by compound and acetylthiocholine addition and measured every 5 to 10 mins for 120 mins by DTNB based Ellman's method
Measurement: Kd = 1220 nM (pChEMBL 5.909999847412109)
Descriptors: MW 391.27, ALogP 2.68, HBA 6, HBD 2, PSA 72.19, QED 0.48
Compound (SMILES): CCOC(=O)/C=C/c1ccc2nc3n(c(=O)c2c1)C1C=CC(F)=CC1C3=O
InChIKey: HXRZECWDORAZCN-XBXARRHUSA-N
Target: Indoleamine 2,3-dioxygenase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P14902
Assay: Inhibition of IDO1 in human HeLa cells
Measurement: IC50 = 20 nM (pChEMBL 7.699999809265137)
Descriptors: MW 366.35, ALogP 2.75, HBA 6, HBD 0, PSA 78.26, QED 0.62
Compound (SMILES): O=C1NC(=O)C(c2cn(CCCn3ccnc3)c3ccc(Br)cc23)=C1c1ccc2ccccc2c1
InChIKey: OJKUBSIIKJVKQP-UHFFFAOYSA-N
Target: Glycogen synthase kinase-3 beta (SINGLE PROTEIN), Homo sapiens
UniProt: P49841
Assay: Inhibition of GSK3beta (unknown origin) activity assessed as fluorescence intensity by ADP-Glo Kinase Assay
Measurement: IC50 = 69 nM (pChEMBL 7.159999847412109)
Descriptors: MW 525.41, ALogP 5.41, HBA 5, HBD 1, PSA 68.92, QED 0.3
Compound (SMILES): CN(C)C/C=C/C(=O)Nc1ccc(C(=O)NC2CCCC(Nc3nccc(-c4c(-c5ccccc5)nn5ccccc45)n3)C2)cc1
InChIKey: ILTRIOQDZUXVFP-OQLLNIDSSA-N
Target: Mitogen-activated protein kinase 8 (SINGLE PROTEIN), Homo sapiens
UniProt: P45983
Assay: Inhibition of His-tagged human recombinant JNK1 expressed in insect cells incubated for 1 hr in presence of ATP by Z'-Lyte assay
Measurement: IC50 = 475 nM (pChEMBL 6.320000171661377)
Descriptors: MW 614.75, ALogP 5.67, HBA 8, HBD 3, PSA 116.55, QED 0.17
Compound (SMILES): CC(C)Cn1c(=O)c2[nH]cnc2n(C)c1=O
InChIKey: DZAZIOFIVCEFLH-UHFFFAOYSA-N
Target: Cystic fibrosis transmembrane conductance regulator (SINGLE PROTEIN), Homo sapiens
UniProt: P13569
Assay: Activation of wildtype CFTR in human Calu-3 cells
Measurement: EC50 = 100000 nM (pChEMBL 4)
Descriptors: MW 222.25, ALogP 0.08, HBA 5, HBD 1, PSA 72.68, QED 0.78
Compound (SMILES): CCOC(=O)c1nc(NCc2ccccc2Cl)c2c(C)noc2n1
InChIKey: ZAGUVQPKPPDOPS-UHFFFAOYSA-N
Target: Solute carrier family 26 member 6 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9BXS9
Assay: Inhibition of SLC26A6 (unknown origin) expressed in rat FRT cells coexpressing YFP halide-sensing protein assessed as iodide-chloride exchange incubated for 2 sec by fluorescence quenching analysis
Measurement: IC50 = 1100 nM (pChEMBL 5.960000038146973)
Descriptors: MW 346.77, ALogP 3.37, HBA 7, HBD 1, PSA 90.14, QED 0.71
Compound (SMILES): COC(=O)C(Cc1ccccc1I)NC(=O)CN(Cc1ccccc1)C(=O)OC(C)(C)C
InChIKey: TUGDQIGXMLHXSL-UHFFFAOYSA-N
Target: Kappa-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41145
Assay: Displacement of [3H]U69593 from human KOR expressed in HEK cell membranes assessed as inhibition constant incubated for 60 mins by microbeta 2 scintillation counting method
Measurement: Ki = 4185 nM (pChEMBL 5.380000114440918)
Descriptors: MW 552.41, ALogP 3.93, HBA 5, HBD 1, PSA 84.94, QED 0.4
Compound (SMILES): CC[C@@H]1C(=O)N(C)c2cnc(Nc3cc4c(cc3OC)N(C(=O)CN3CCN(C(C)=O)CC3)CC4)nc2N1Cc1cccs1
InChIKey: HYADALKUILXFKH-XMMPIXPASA-N
Target: Serine/threonine-protein kinase PLK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P53350
Assay: Inhibition of PLK1 (unknown origin) preincubated for 10 mins followed by substrate and ATP addition and measured after 60 mins by ADP-Glo kinase assay
Measurement: IC50 = 3.12 nM (pChEMBL 8.510000228881836)
Descriptors: MW 618.76, ALogP 3.11, HBA 10, HBD 1, PSA 114.45, QED 0.41
Compound (SMILES): COCCNC(=N)NCCC[C@H](N)c1noc(=O)[nH]1
InChIKey: FHZVWHPQDRDCQT-ZETCQYMHSA-N
Target: N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: O94760
Assay: Inhibition of recombinant human DDAH1 expressed in HEK293 cells using ADMA as substrate assessed as inhibition constant preincubated for 5 mins
Measurement: Ki = 7000 nM (pChEMBL 5.159999847412109)
Descriptors: MW 272.31, ALogP -1.1, HBA 6, HBD 5, PSA 142.05, QED 0.23
Compound (SMILES): CC(C)(F)CNCc1ccc2nc(CNC(=O)c3cc(=O)n4ccccc4n3)cn2c1
InChIKey: CEVRESVNJLXVDM-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 = 61.1 nM (pChEMBL 7.210000038146973)
Descriptors: MW 422.46, ALogP 2.11, HBA 7, HBD 2, PSA 92.8, QED 0.48
Compound (SMILES): O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccccc1CN1CCn2nncc2C1
InChIKey: NAEYKCMDHVJQFQ-UHFFFAOYSA-N
Target: E3 ubiquitin-protein ligase CBL-B (SINGLE PROTEIN), Homo sapiens
UniProt: Q13191
Assay: Displacement of FAM-labeled probe from recombinant biotinylated Cbl-b (unknown origin) expressed in Escherichia coli BL21(DE3) Tuner cells by TR-FRET assay
Measurement: IC50 = 300 nM (pChEMBL 6.519999980926514)
Descriptors: MW 491.56, ALogP 2.84, HBA 7, HBD 2, PSA 104.51, QED 0.45
Compound (SMILES): CCN(CC)CCCNc1cc2nc(/C=C/c3ccc(C(C)C)cc3)n(Cc3ccccc3Br)c(=O)c2cc1F
InChIKey: DKAGTUPMZAGBHL-SAPNQHFASA-N
Target: RecQ-like DNA helicase BLM (SINGLE PROTEIN), Homo sapiens
UniProt: P54132
Assay: Inhibition of His-tagged BLM (unknown origin) expressed in Escherichia coli BL21 (DE3) using 5'-biotin-labeled duplex forked-DNA as substrate incubated for 10 mins followed by substrate addition measured after 30 mins in presence of ATP by electrophoretic mobility shift assay
Measurement: IC50 = 2900 nM (pChEMBL 5.539999961853027)
Descriptors: MW 605.6, ALogP 7.78, HBA 5, HBD 1, PSA 50.16, QED 0.17
Compound (SMILES): CCN(CC)C(=O)c1cc(-c2cccs2)nc2c1c(C)nn2-c1ccccc1
InChIKey: ROPKBTAXRMZNIJ-UHFFFAOYSA-N
Target: Dual 3',5'-cyclic-AMP and -GMP phosphodiesterase 11A (SINGLE PROTEIN), Homo sapiens
UniProt: Q9HCR9
Assay: Inhibition of recombinant N-terminal GST-tagged human PDE11A4 (1 to 943 residues) expressed in Sf9 cells using cGMP and cAMP as substrates by Ba(OH)2 precipitation method
Measurement: IC50 = 420 nM (pChEMBL 6.380000114440918)
Descriptors: MW 390.51, ALogP 4.94, HBA 5, HBD 0, PSA 51.02, QED 0.48
Compound (SMILES): C[C@H](C[C@@H](F)C(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
InChIKey: QEHUVDYKCYBWLR-SWSYAYITSA-N
Target: G-protein coupled bile acid receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q8TDU6
Assay: Agonist activity at TGR5 in human NCI-H716 cells assessed as increase in cAMP level incubated for 60 mins by HTR-FRET assay
Measurement: EC50 > 100000 nM (pChEMBL 4)
Descriptors: MW 426.57, ALogP 3.4, HBA 4, HBD 4, PSA 97.99, QED 0.55
Compound (SMILES): O=C1Nc2cc(CS(=O)(=O)c3c(Cl)cccc3Cl)ccc2S/C1=C\c1ccc(O)c([N+](=O)[O-])c1
InChIKey: VFLPOFHPMNYCOH-JMIUGGIZSA-N
Target: Casein kinase II subunit alpha' (SINGLE PROTEIN), Homo sapiens
UniProt: P19784
Assay: Inhibition of CK2alpha2 (unknown origin)
Measurement: IC50 = 5 nM (pChEMBL 8.300000190734863)
Descriptors: MW 537.4, ALogP 5.67, HBA 7, HBD 2, PSA 126.61, QED 0.24
Compound (SMILES): CCN(CC)CCCC(C)Nc1cnc(C(=O)Nc2ccc(OC)c3ccc(OC)nc23)cn1
InChIKey: ZUGAAXJGAMPFAI-UHFFFAOYSA-N
Target: Sigma non-opioid intracellular receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q99720
Assay: Displacement of [3H](+)-pentazocine from human sigma 1 receptor transfected in human HEK293T cells assessed as inhibition constant by radioligand competition binding assay
Measurement: Ki = 132 nM (pChEMBL 6.880000114440918)
Descriptors: MW 466.59, ALogP 4.22, HBA 8, HBD 2, PSA 101.5, QED 0.41
Compound (SMILES): O=C(O)c1ccc(CCNC(=O)c2cc(O)ccc2NC(=O)c2cc(Br)c(Br)[nH]2)cc1
InChIKey: XSDHEUPUYYSZME-UHFFFAOYSA-N
Target: DNA topoisomerase 2-alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P11388
Assay: Inhibition of human DNA topoisomerase 2 alpha assessed as relaxation of supercoiled plasmid pNO1 DNA incubated for 30 mins by fluorescence based analysis
Measurement: IC50 = 22000 nM (pChEMBL 4.659999847412109)
Descriptors: MW 551.19, ALogP 4.17, HBA 4, HBD 5, PSA 131.52, QED 0.28
Compound (SMILES): CCCCCCOc1ccc(OC(C)C(=O)Cn2nnc(CCCC(=O)O)n2)cc1
InChIKey: XGBDYLDQJQGNAU-UHFFFAOYSA-N
Target: Fatty-acid amide hydrolase 1 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P97612
Assay: Inhibition of rat brain microsome FAAH using N-(2-hydroxyethyl)-4-pyren-1-ylbutanamide as substrate incubated for 60 mins by RP-HPLC analysis
Measurement: IC50 = 34 nM (pChEMBL 7.46999979019165)
Descriptors: MW 418.49, ALogP 3.08, HBA 8, HBD 1, PSA 116.43, QED 0.44