lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(Cc3cccc(Oc4ccccc4)c3)CC2)C1
InChIKey: YUJWHVPMAKCLQL-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK2 (SINGLE PROTEIN), Homo sapiens
UniProt: O60674
Assay: In Vitro JAK Kinase Assay: Compounds herein were tested for inhibitory activity of JAK targets according to the following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104. The catalytic domains of human JAK1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a. 781-1124) with an N-terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic activity of JAK1, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF). IC50s of compounds were measured for each kinase in the 40 microL reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. For the 1 mM IC50 measurements, ATP concentration in the reactions was 1 mM. Reactions were carried out at room temperature for 1 hr and then stopped with 20 μL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, Mass.). Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, Mass.).
Measurement: IC50 = 25 nM (pChEMBL 7.599999904632568)
Descriptors: MW 544.66, ALogP 5.2, HBA 8, HBD 1, PSA 98.89, QED 0.29
Compound (SMILES): C[C@H](Nc1ncnc(N)c1C#Cc1cnccn1)c1nc2cccc(F)c2c(=O)n1-c1cc(F)cc(F)c1
InChIKey: HMFNXNYKXFFOHC-AWEZNQCLSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) Assay: PI3K isoforms were assayed under initial rate conditions in the presence of 25 mM Hepes (pH 7.4), and 2xKm ATP (100-300 uM), 10 uM PIP2, 5% glycerol, 5 mM MgCl2, 50 mM NaCl, 0.05% (v/v) Chaps, 1 mM dithiothreitol, 1% (v/v) DMSO at the following concentrations for each isoform: PI3K alpha, beta, delta, and gamma at 50 picomolar (pM) and PI3Kgamma at 2 nanomolar (nM). After an assay reaction time of 30 minutes at 25° C., reactions were terminated with a final concentration of 10 mM EDTA, 10 nM labeled-PIP3, and 35 nM Europium labeled GRP-1 detector protein before reading TR-FRET on an Envision plate reader (Ex: 340 nm; Em: 615/665 nm; 100 us delay and 500 us read window).
Measurement: IC50 > 1000 nM (pChEMBL 6)
Descriptors: MW 514.47, ALogP 3.54, HBA 9, HBD 2, PSA 124.5, QED 0.35
Compound (SMILES): CN1CCN(Cc2ccc(-c3cn4c5nc(ncc35)NCCCCCCC(O)CCC4)cc2)CC1
InChIKey: ORJFNGOUYHBFPE-UHFFFAOYSA-N
Target: Tyrosine-protein kinase receptor UFO (SINGLE PROTEIN), Homo sapiens
UniProt: P30530
Assay: Inhibition of Axl (unknown origin) by microfluidic capillary electrophoresis assay
Measurement: IC50 = 50 nM (pChEMBL 7.300000190734863)
Descriptors: MW 476.67, ALogP 4.36, HBA 7, HBD 2, PSA 69.45, QED 0.59
Compound (SMILES): COc1c(Nc2ncc(Cl)c(Nc3ccccc3-c3nccn3C)n2)ccc2c1CCCC(N1CCN(CCO)CC1)C2
InChIKey: COZPORUDEQRJMN-UHFFFAOYSA-N
Target: Focal adhesion kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: Q05397
Assay: Inhibition of human FAK expressed in baculovirus after 30 mins using biotinyl-amino-hexanoyl-EQEDEPEGDYFEWLE-amide as substrate by TRF assay
Measurement: IC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 603.17, ALogP 4.88, HBA 10, HBD 3, PSA 103.6, QED 0.23
Compound (SMILES): COc1ccc(N2CCC(N3CCCCC3)CC2)cc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
InChIKey: YIEAIQUVMIMQLN-UHFFFAOYSA-N
Target: Receptor tyrosine-protein kinase erbB-2 (SINGLE PROTEIN), Homo sapiens
UniProt: P04626
Assay: Inhibition of recombinant human full length ErbB2 expressed in baculovirus expression system assessed as decrease in transfer of gamma-phosphate from ATP onto tyrosine residue of biotinylated peptide substrate preincubated for 1 hr followed by substrate addition measured after 90 mins by HTRF method
Measurement: IC50 < 1000 nM (pChEMBL 6)
Descriptors: MW 744.85, ALogP 8.2, HBA 10, HBD 2, PSA 109.15, QED 0.14
Compound (SMILES): NC(=O)c1cccc([C@H]2C[C@H]3CC[C@@H](C2)N3CCN(CCc2ccccc2)C(=O)CO)c1
InChIKey: GSSMSYOYNFKOTD-BKFWDETESA-N
Target: Delta-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P41143
Assay: Displacement of [3H]-DPN from recombinant human delta opioid receptor expressed in CHO-K1 cell membranes by radioligand binding assay
Measurement: Ki = 19.95 nM (pChEMBL 7.699999809265137)
Descriptors: MW 435.57, ALogP 2.56, HBA 4, HBD 2, PSA 86.87, QED 0.63
Compound (SMILES): COc1cc(OC)cc(N(CCN2CCC(O)C2)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1.Cl
InChIKey: ISVOAPUXDBEYPJ-UHFFFAOYSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 474.57, ALogP 3.25, HBA 9, HBD 1, PSA 88.77, QED 0.42
Compound (SMILES): O=C(NCCS(=O)(=O)Nc1ccc(-n2ccncc2=O)cc1)c1ccc(Cl)s1
InChIKey: YSWODTNWYVODPG-UHFFFAOYSA-N
Target: Coagulation factor X (SINGLE PROTEIN), Homo sapiens
UniProt: P00742
Assay: Biochemical assay using fluorogenic peptide substrate.Step 1: Compound transfer to plate (50 nl).Step 2: Dilute FXa in Assay Buffer.Step 3: Dilute substrate in Assay Buffer.Step 4: Add equal volumes to Assay plate (total assay volume 10 uL).Step 5: Centrifuge plate, 1 min, 1000 rpm.Step 6: Detect fluorescence signal: ex: 320 nm; Em. 405 nm (EnVision), every 10 min. 30 min pre-incubation of enzyme with compound and 15 min reaction time after substrate addition.
Measurement: IC50 = 29.7 nM (pChEMBL 7.53000020980835)
Descriptors: MW 438.92, ALogP 2.12, HBA 7, HBD 2, PSA 110.16, QED 0.59
Compound (SMILES): Cc1ccc2c(c1)C(=O)N(C)c1cnc(Nc3cccc(S(=O)(=O)N4CCC(O)CC4)c3)nc1N2C
InChIKey: GHKMIOAEPALCFS-UHFFFAOYSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P42336
Assay: Inhibition of human PI3Kalpha (R108 to N1068 residues) expressed in mammalian expression system incubated for 60 mins by ADAPTA assay
Measurement: IC50 = 55 nM (pChEMBL 7.260000228881836)
Descriptors: MW 508.6, ALogP 3.03, HBA 8, HBD 2, PSA 118.97, QED 0.55
Compound (SMILES): CN(C)C1(c2ccccc2)CCC2(CC1)OCCc1c2[nH]c2ccccc12
InChIKey: PICPCIFZWHBKPD-UHFFFAOYSA-N
Target: Mu-type opioid receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P35372
Assay: Binding Assay: The receptor affinity for the human mu-opiate receptor was determined in a homogeneous batch in microtitre plates. For this, dilution series of the particular spirocyclic cyclohexane derivative to be tested were incubated in a total volume of 250 ul for 90 minutes at room temperature with a receptor membrane preparation (15-40 ug protein per 250 ul incubation batch) of CHO-K1 cells, which express the human mu-opiate receptor (RB-HOM receptor membrane preparation of NEN, Zaventem, Belgium), in the presence of 1 nmol/l of the radioactive ligand [3H]-naloxone (NET719, NEN, Zaventem, Belgium) and of 1 mg WGA-SPA beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg, Germany). 50 mmoles/l Tris-HCl supplemented with 0.05 wt. % sodium azide and with 0.06 wt. % bovine serum albumin was used as the incubation buffer. 25 umoles/l naloxone was additionally added for determination of the non-specific binding.
Measurement: Ki = 1.3 nM (pChEMBL 8.890000343322754)
Descriptors: MW 360.5, ALogP 4.97, HBA 2, HBD 1, PSA 28.26, QED 0.7
Compound (SMILES): O=C(NCc1ccccc1)Nc1ccc(C2CCNC2)cc1
InChIKey: WGWIXBVIMOHDAY-UHFFFAOYSA-N
Target: Non-receptor tyrosine-protein kinase TYK2 (SINGLE PROTEIN), Homo sapiens
UniProt: P29597
Assay: Biochemical JAK and Tyk2 Kinase Assays: A panel of four LanthaScreen JAK biochemical assays (JAK1, 2, 3 and Tyk2) were carried in a common kinase reaction buffer (50 mM HEPES, pH 7.5, 0.01% Brij-35, 10 mM MgCl2, and 1 mM EGTA). Recombinant GST-tagged JAK enzymes and a GFP-tagged STAT1 peptide substrate were obtained from Life Technologies. Serially or discretely diluted compounds were pre-incubated with each of the four JAK enzymes and the substrate in white 384-well microplates (Corning) at ambient temperature for 1 h. ATP was subsequently added to initiate the kinase reactions in 10 μL total volume, with 1% DMSO. The final enzyme concentrations for JAK1, 2, 3 and Tyk2 are 4.2 nM, 0.1 nM, 1 nM, and 0.25 nM respectively; the corresponding Km ATP concentrations used are 25 μM, 3 μM, 1.6 μM, and 10 μM; while the substrate concentration is 200 nM for all four assays. Kinase reactions were allowed to proceed for 1 hour at ambient temperature before a 10 μL preparation of EDTA (10 mM final concentration) and Tb-anti-pSTAT1 (pTyr701) antibody (Life Technologies, 2 nM final concentration) in TR-FRET dilution buffer (Life Technologies) was added. The plates were allowed to incubate at ambient temperature for 1 h before being read on the EnVision reader (Perkin Elmer). Emission ratio signals (520 nm/495 nm) were recorded and utilized to calculate the percent inhibition values based on DMSO and background controls.For dose-response analysis, percent inhibition data were plotted vs. compound concentrations, and IC50 values were determined from a 4-parameter robust fit model with the Prism software (GraphPad Software). Results were expressed as pIC50 (negative logarithm of IC50) and subsequently converted to pKi (negative logarithm of dissociation constant, Ki) using the Cheng-Prusoff equation.
Measurement: Ki > 100 nM (pChEMBL 7)
Descriptors: MW 295.39, ALogP 3.09, HBA 2, HBD 3, PSA 53.16, QED 0.81
Compound (SMILES): COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCCC1CN(C)C(C)(C)CO1
InChIKey: NTVIDJBDSIQHHB-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Inhibition of recombinant human N-terminal GST-fused KDR (D807 to V1356 residues) expressed in baculovirus infected Escherichia coli or insect Sf9 cells using poly-EY as substrate after 240 mins by luciferase coupled chemiluminescence assay
Measurement: IC50 = 50 nM (pChEMBL 7.300000190734863)
Descriptors: MW 491.42, ALogP 5.57, HBA 7, HBD 1, PSA 68.74, QED 0.46
Compound (SMILES): N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3ccc(O)c(Cl)c3)CC2)C1
InChIKey: XVKIJNUDBATXCI-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: Inhibition of human N-terminal His-tagged JAK1 catalytic domain (837 to 1142 residues) expressed in baculovirus infected insect cells assessed as decrease in phosphorylation of biotinylated peptide substrate after 1 hr in presence of 1 mM ATP by HTRF method
Measurement: IC50 <= 5 nM (pChEMBL 8.300999641418457)
Descriptors: MW 516.99, ALogP 3.41, HBA 8, HBD 2, PSA 126.96, QED 0.42
Compound (SMILES): O=C(O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2onc(-c3ccccc3)c2C(F)(F)F)C1
InChIKey: IVRVCMWFTIBONM-UHFFFAOYSA-N
Target: Sphingosine 1-phosphate receptor 3 (SINGLE PROTEIN), Homo sapiens
UniProt: Q99500
Assay: Agonist activity at human S1P3 expressed in CHO cell membranes assessed as stimulation of [35S]-GTPgamma-S binding measured after 45 mins by liquid scintillation counting method
Measurement: EC50 = 4400 nM (pChEMBL 5.360000133514404)
Descriptors: MW 495.46, ALogP 5.3, HBA 6, HBD 1, PSA 92.6, QED 0.4
Compound (SMILES): COc1cc2c(Nc3cc(Cl)c(Br)cc3F)ncnc2cc1OC[C@H]1CN2CCOC[C@H]2CO1
InChIKey: NJQIBYWJBXKSRO-UONOGXRCSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Inhibition of recombinant human N-terminal GST-fused KDR (D807 to V1356 residues) expressed in baculovirus infected Escherichia coli or insect Sf9 cells using poly-EY as substrate after 240 mins by luciferase coupled chemiluminescence assay
Measurement: IC50 = 50 nM (pChEMBL 7.300000190734863)
Descriptors: MW 553.82, ALogP 4.42, HBA 8, HBD 1, PSA 77.97, QED 0.45
Compound (SMILES): N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3ccc(-c4ccc(C#N)c(F)c4)c(F)c3)CC2)C1
InChIKey: IBCNFSKVJJJJTL-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: In vitro JAK Kinase Assay: The catalytic domains of human JAK1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a. 781-1124) with an N-terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic activity of JAK1, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF). IC50s of compounds were measured for each kinase in the 40 microL reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. For the 1 mM IC50 measurements, ATP concentration in the reactions was 1 mM. Reactions were carried out at room temperature for 1 hr and then stopped with 20 μL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, Mass.). Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, Mass.)
Measurement: IC50 < 5 nM (pChEMBL 8.300999641418457)
Descriptors: MW 603.64, ALogP 4.87, HBA 8, HBD 1, PSA 130.52, QED 0.29
Compound (SMILES): COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1noc(C2CCNCC2)n1
InChIKey: LFVVFUDFYJQWPX-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: AlphaScreen Assay: In AlphaScreen, when the donor and acceptor beads are close in proximity, a series of photochemical events will give rise to a fluorescent signal upon light activation. Here we use biotinylated poly-(Glu, Tyr) 4:1 as the kinase substrate, streptavidin-coated donor beads and anti-phosphortyrosine antibody PY100-coated acceptor beads. Upon phosphorylation, the peptide substrate can bind to both donor and acceptor beads, thus gives rise to fluorescence. Compounds, ATP, biotinylated poly-(Glu, Tyr) and kinases are mixed in a volume of 20 μL for 1 hr at ambient temperature using Greiner 384-well white clear bottom medium binding plates. Then 10 uL solution containing 15-30 mg/mL AlphaScreen beads, 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3% BSA and 0.03% Tween-20 is added to each well. After 2-16 hr incubation of the beads, plates are read in a Perkin Elmer AlphaQuest reader (available from PerkinElmer Life and Analytical Sciences, Inc., of Boston Mass.).
Measurement: IC50 < 50 nM (pChEMBL 7.301000118255615)
Descriptors: MW 501.37, ALogP 5.12, HBA 9, HBD 2, PSA 107.22, QED 0.36
Compound (SMILES): c1csc(Cc2cccc3c2CCC2CNCCN32)c1
InChIKey: NNRMMTGPLBXKIO-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 2A (SINGLE PROTEIN), Homo sapiens
UniProt: P28223
Assay: Agonist activity at 5-HT2A receptor (unknown origin) expressed in HEK293 cells assessed as [3H]inositol phosphate accumulation after 2 hrs by scintillation counting
Measurement: EC50 = 79.43 nM (pChEMBL 7.099999904632568)
Descriptors: MW 284.43, ALogP 3.06, HBA 3, HBD 1, PSA 15.27, QED 0.91
Compound (SMILES): CCCn1cc(-c2cnc3ccc(N(CCN)c4cc(OC)cc(OC)c4)cc3n2)cn1.Cl
InChIKey: FYIRHIZOHYRDDH-UHFFFAOYSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 432.53, ALogP 4.02, HBA 8, HBD 1, PSA 91.32, QED 0.43
Compound (SMILES): C=C(C)c1cc(-c2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)nc(N2CCOCC2)n1
InChIKey: NZQDZMBWHLVRCS-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase B-raf (SINGLE PROTEIN), Homo sapiens
UniProt: P15056
Assay: In Vitro Enzyme Assay: Final assay conditions were 4 pM cRaf, 3 uM ATP, 10 nM biotin tagged MEK1 kinase dead protein substrate. Reactions were performed in Greiner384 well plates, catalog #784075. Reaction buffer was 50 mM Tris, pH 7.5, 50 mM NaCl, 10 mM MgCl2, 0.01% Tween-20, 0.05% BSA and 1 mM DTT. 5 ul of 2×cRaf plus MEK1 were dispensed into plates containing 0.25 ul of compound in 100% DMSO and incubated at room temperature for 30 minutes. Reactions were started by addition of 5 ul of 2×ATP. Reactions were run for two hours and terminated by addition of 10 ul of 2× antibody and Alphascreen bead mixture in Stop Buffer. Stop Buffer was 50 mM Tris, pH 7.5, 0.005% Tween-20, 25 mM EDTA.
Measurement: IC50 = 0.422 nM (pChEMBL 9.380000114440918)
Descriptors: MW 482.51, ALogP 5.59, HBA 5, HBD 1, PSA 67.35, QED 0.51
Compound (SMILES): CC(=O)N1CCc2[nH]nc(Nc3ccccc3)c2C1
InChIKey: ZXIJCVCJLDGJRX-UHFFFAOYSA-N
Target: Bromodomain-containing protein 8 (SINGLE PROTEIN), Homo sapiens
UniProt: Q9H0E9
Assay: Displacement of biotinylated ligand from recombinant His-tagged BRD8 bromodomain-1 (unknown origin) measured after 10 mins by TR-FRET assay
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 256.31, ALogP 2.06, HBA 3, HBD 2, PSA 61.02, QED 0.86
Compound (SMILES): Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CCC3)c(Oc3ccc(C#N)cc3)c(Cl)c2c1
InChIKey: HGMJOSNOVDDGAZ-UHFFFAOYSA-N
Target: Nuclear receptor ROR-gamma (SINGLE PROTEIN), Homo sapiens
UniProt: P51449
Assay: RORγt Reporter Assay: The reporter assay was performed by transiently transfecting HEK293T cells with 5 μg of pBIND-RORγt LBD or pBIND-RORγt LBD-AF2 and 5 μg pGL4.31 (Promega Cat no. C935A) using Fugene 6 (Invitrogen Cat no. E2691) at a 1:6 ratio of DNA: Fugene 6 in a T-75 flask in which cells were at least 80% confluent. Twenty four hours after bulk transfection, cells were plated into 96-well plates at 50,000 cells/well in phenol-red free DMEM containing 5% Lipid Reduced FCS and Pen/Strep. Six hours after plating, cells were treated with compounds for 24 hours. Media was removed and cells were lysed with 50 μL 1x Glo Lysis Buffer (Promega). Dual Glo Luciferase Reagent (50 μL/well) was then added and firefly luciferase luminescence was read on an Envision after a ten minute incubation. Finally, Stop and Glo reagent (50 μL/well) was added and renilla luciferase luminescence was read on an Envision after a ten minute incubation.
Measurement: IC50 = 18 nM (pChEMBL 7.75)
Descriptors: MW 590.99, ALogP 6.19, HBA 8, HBD 1, PSA 100.09, QED 0.25
Compound (SMILES): C=CC(=O)Nc1cccc(-n2c(NC(=O)c3cccc(C(F)(F)F)c3)nc3cc(C)ccc32)c1
InChIKey: PSCDDKKRCVRBLR-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: Inhibition of wild type EGFR phosphorylation in human HaCaT cells incubated for 3 hrs by ELISA method
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 464.45, ALogP 5.73, HBA 4, HBD 2, PSA 76.02, QED 0.37
Compound (SMILES): CC(C)Oc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCC1CNCCO1
InChIKey: VKZGMXBQSCMMFS-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Inhibition of recombinant human N-terminal GST-fused KDR (D807 to V1356 residues) expressed in baculovirus infected Escherichia coli or insect Sf9 cells using poly-EY as substrate after 240 mins by luciferase coupled chemiluminescence assay
Measurement: IC50 < 50 nM (pChEMBL 7.301000118255615)
Descriptors: MW 463.37, ALogP 4.83, HBA 7, HBD 2, PSA 77.53, QED 0.52
Compound (SMILES): CC(C)[C@@H]1c2nn(-c3cccc(S(C)(=O)=O)c3)cc2CN1c1nccc(C(F)(F)F)n1
InChIKey: WZQNVHXAZPMTQI-GOSISDBHSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin)
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 451.47, ALogP 3.8, HBA 7, HBD 0, PSA 80.98, QED 0.6
Compound (SMILES): COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](N4CCN(S(C)(=O)=O)CC4)CN3C(=O)C3CCN(C(=N)N)CC3)[nH]2)cc1
InChIKey: DDRMNRTXBYRQBR-GMAHTHKFSA-N
Target: Coagulation factor XI (SINGLE PROTEIN), Homo sapiens
UniProt: P03951
Assay: In Vitro Factor XIa Enzyme assay: Inhibitory activities of compounds of the present invention against factor XIa, Xa, XIIa, IXa, VIIa, plasma kallikrein or thrombin were evaluated using appropriate purified proteases and synthetic substrates. The rate of hydrolysis of the chromogenic substrate by the relevant protease was continuously measured at 405 nm. Inhibitory activity against each enzyme was calculated as % inhibition using the equation described below. % Inhibition=[[(rate without compound)−(rate with compound)]/(rate without compound)]×100%. Each half maximal inhibitory concentration (IC50) value was determined by plotting the concentration of compound of the invention against the % inhibition.Human Factor XIa (Haematologic Technologies Inc.) activity was measured at an enzyme concentration of 0.1 U/mL in 150 mM NaCl, 5 mM KCl, 1 mg/mL PEG6000, 50 mM HEPES-NaOH (pH7.4) with 300 μM S-2366 (pyroGlu-Pro-Arg-pNA, Chromogenix).
Measurement: IC50 = 7.4 nM (pChEMBL 8.130000114440918)
Descriptors: MW 601.73, ALogP 1.08, HBA 8, HBD 4, PSA 181.05, QED 0.28
Compound (SMILES): CS(=O)(=O)N1CCC(C(=O)N2CC[C@](c3ccc(C(F)(C(F)(F)F)C(F)(F)F)cc3)(S(=O)(=O)c3ccc(F)cc3)C2)CC1
InChIKey: WHXSTZQJSMXRER-QHCPKHFHSA-N
Target: Oxysterols receptor LXR-beta (SINGLE PROTEIN), Homo sapiens
UniProt: P55055
Assay: Agonist activity at LXRbeta (unknown origin) expressed in African green monkey CV1 cells
Measurement: EC50 > 7500 nM (pChEMBL 5.125)
Descriptors: MW 662.62, ALogP 4.69, HBA 5, HBD 0, PSA 91.83, QED 0.33
Compound (SMILES): CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2/C=C/Cc2ccc(C(=O)O)s2)cc1
InChIKey: WWZDFNDWWMQENR-ZNNKIELSSA-N
Target: Prostaglandin E2 receptor EP2 subtype (SINGLE PROTEIN), Homo sapiens
UniProt: P43116
Assay: Agonist activity at human recombinant EP2 receptor expressed in HEK-EBNA cells incubated for 30 mins by cAMP accumulation assay
Measurement: EC50 = 15 nM (pChEMBL 7.820000171661377)
Descriptors: MW 427.57, ALogP 5.35, HBA 4, HBD 2, PSA 77.84, QED 0.4
Compound (SMILES): CN(c1ccc(Br)cn1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
InChIKey: GKWPRMUJKHEUNS-GFCCVEGCSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: Enzymatic Assay: JAK1/2/3 kinase assay are performed in vitro using Kit-Tyr 6 Peptide (Invitrogen, Cat. No. PV4122). TYK2 kinase assay are performed in vitro using Z′-LYTE Kinase Assay Kit-Tyr 3 Peptide (Invitrogen, Cat. No. PV3192). Recombinant human JAK1/2/3 or TYK2 catalytic domains are from Invitrogen (Cat No. PV4774/PV4210/PV3855/PV4790); All reactions (20 μL) are started by adding 2.5 μL of the testing compound in 4% DMSO solution, 5 μL of Kinase/Peptide substrate Mixture (3.2, 0.04, 0.2 or 8 μg/mL for Recombinant human JAK1/2/3 catalytic domains, 4 μM for Z-LYTE Tyr 6 peptide or Z-LYTE Tyr 3 peptide) or Phospho-Peptide solution (Invitrogen, Cat. No. PV3192, diluted with 1.33× Kinase Buffer), 2.5 μL ATP Solution (300/100/40/100 μM, JAK1/JAK2/JAK3/TYK2) or 1.33× Kinase Buffer (Invitrogen, Cat. No. PV3189, 5× diluted with distilled water). The 384-well assay plate (Corning, Cat. No. 3575) is mixed and incubated at room temperature for 1 hour. 5 μL of the Development Solution (Dilute Development Reagent A (Cat. No. PV3297) is diluted to 1/64 with Development Buffer (Cat. No. PV3127) for JAK1, JAK2 and JAK3 assay; Development Reagent A (Cat. No. PV3297) is diluted to 1/2048 with Development Buffer (Cat. No. PV3127) for TYK2 assay. The diluted Development Solution is then added to each well, mixed and incubated at room temperature for another 1 hour. The kinase reaction is then stopped by adding 5 μL of the Stop Reagent (Invitrogen, Cat. No. PV3094), and the plate is read with Wallac 1420 VICTOR3 Multilabel Counter (PerkinElmer) at 445 nm and 520 nm fluorescence. All compounds are initially tested at 8 different concentrations (1 μM down to 0.0003 μM) using a 1:3 serial dilution scheme.
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 373.26, ALogP 2.83, HBA 5, HBD 1, PSA 60.94, QED 0.77
Compound (SMILES): COc1cc2c(Nc3ccc(Cl)c(Cl)c3F)ncnc2cc1OC[C@@H]1CN2CCC[C@H]2CO1
InChIKey: REMMHMJADZNMGO-KBPBESRZSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Inhibition of recombinant human N-terminal GST-fused KDR (D807 to V1356 residues) expressed in baculovirus infected Escherichia coli or insect Sf9 cells using poly-EY as substrate after 240 mins by luciferase coupled chemiluminescence assay
Measurement: IC50 < 50 nM (pChEMBL 7.301000118255615)
Descriptors: MW 493.37, ALogP 5.07, HBA 7, HBD 1, PSA 68.74, QED 0.48
Compound (SMILES): COc1cc(OC)cc(N(CC#Cc2cc(OC)ncn2)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1
InChIKey: SDIZOFZVSQJIHJ-UHFFFAOYSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 = 3162.28 nM (pChEMBL 5.5)
Descriptors: MW 507.55, ALogP 4.04, HBA 10, HBD 0, PSA 100.31, QED 0.3
Compound (SMILES): O=C(Nc1cccc(C(F)(F)F)c1)N1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
InChIKey: YSEXRGLTJSGRFZ-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: Enzyme Assay: JAK1, JAK2, JAK3 and Tyk2 were purchased from Carna Biosciences, Inc. As the substrate, LANCE Ultra ULight-JAK1 Peptide (manufactured by PerkinElmer Co., Ltd. (PE)) was used. Dilute solutions of compounds and enzymes in assay buffer (50 mM HEPES pH7.5, 1 mM EGTA, 1 mM MgCl2, 2 mM DTT, 0.01% Tween20) were dispensed into wells of a 384-well black plate. After 5 minutes of preincubation, dilute solutions of the substrate and ATP (adenosine triphosphate) were added at a final concentration of 100 μM, and the plate was incubated at room temperature for 2 hours. After addition of a termination reagent containing EDTA (ethylenediamine tetraacetic acid) at a final concentration of 10 mM, LANCE Eu-W1024 Anti-phosphotyrosine (PT66) (manufactured by PE) was added, and after 1 hour of incubation, the fluorescences were measured with ARVO-HTS. From the plot of logarithm of a compound concentration and inhibitory activity, the IC50 was calculated.
Measurement: IC50 = 13 nM (pChEMBL 7.889999866485596)
Descriptors: MW 429.41, ALogP 4.04, HBA 5, HBD 2, PSA 91.21, QED 0.5
Compound (SMILES): [2H]C([2H])([2H])n1cc(-c2ccc3ncc(N(CCO)c4cc(OC)cc(OC)c4)nc3c2)cn1
InChIKey: XBRAGXSHNWCDEC-FIBGUPNXSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 = 7943.28 nM (pChEMBL 5.099999904632568)
Descriptors: MW 405.46, ALogP 3.18, HBA 8, HBD 1, PSA 85.53, QED 0.51
Compound (SMILES): COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1nc(N2CCN(C)CC2)no1
InChIKey: UNVZWJFKXAEDKM-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Inhibition of recombinant human N-terminal GST-fused KDR (D807 to V1356 residues) expressed in baculovirus infected Escherichia coli or insect Sf9 cells using poly-EY as substrate after 240 mins by luciferase coupled chemiluminescence assay
Measurement: IC50 < 50 nM (pChEMBL 7.301000118255615)
Descriptors: MW 516.39, ALogP 4.4, HBA 10, HBD 1, PSA 101.67, QED 0.38
Compound (SMILES): CCOc1cc(F)ccc1-c1nc(Nc2cc(F)cc(CS(C)(=N)=O)c2)ncc1F
InChIKey: XOTQSFMYDHXIOI-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P24941
Assay: CDK2/CycE Kinase Assay: Recombinant fusion proteins of GST and human CDK2 and of GST and human CycE, expressed in insect cells (Sf9) and purified by Glutathion-Sepharose affinity chromatography, were purchased from ProQinase GmbH (Freiburg, Germany). As substrate for the kinase reaction biotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amid form) was used which can be purchased e.g. form the company JERINI Peptide Technologies (Berlin, Germany)For the assay 50 nl of a 100 fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 ul of a solution of CDK2/CycE in aqueous assay buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl2, 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were added and the mixture was incubated for 15 min at 22 C. to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction.
Measurement: IC50 = 260 nM (pChEMBL 6.579999923706055)
Descriptors: MW 436.46, ALogP 4.88, HBA 6, HBD 2, PSA 87.96, QED 0.55
Compound (SMILES): COc1ccc(F)c(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)c1
InChIKey: BRGQAIVRMIFYPX-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: Inhibition of human N-terminal His-tagged JAK1 catalytic domain (837 to 1142 residues) expressed in baculovirus infected insect cells assessed as decrease in phosphorylation of biotinylated peptide substrate after 1 hr in presence of 1 mM ATP by HTRF method
Measurement: IC50 > 5 nM (pChEMBL 8.300999641418457)
Descriptors: MW 514.57, ALogP 3.2, HBA 8, HBD 1, PSA 115.96, QED 0.42
Compound (SMILES): COc1cc2c(cc1OC)CN(CCCCc1nc3cc(Cl)ccc3s1)CC2.Cl
InChIKey: CIEYQJXJQBPJAX-UHFFFAOYSA-N
Target: 5-hydroxytryptamine receptor 2A (SINGLE PROTEIN), Homo sapiens
UniProt: P28223
Assay: Displacement of [3H]-ketanserin from human 5-HT2A receptor by liquid scintillation counting method
Measurement: Ki = 667 nM (pChEMBL 6.179999828338623)
Descriptors: MW 416.97, ALogP 5.35, HBA 5, HBD 0, PSA 34.59, QED 0.49
Compound (SMILES): CCCCCC(O)c1ccc([C@@H]2[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@@H]2Cl)cc1
InChIKey: ZZPVJHFTTJXWMD-LQUPIGEUSA-N
Target: Prostaglandin E2 receptor EP4 subtype (SINGLE PROTEIN), Homo sapiens
UniProt: P35408
Assay: Agonist activity at human recombinant EP4 receptor expressed in HEK293 cells assessed as effect on calcium accumulation by Fluo-4 AM dye based FLIPR assay
Measurement: EC50 = 10000 nM (pChEMBL 5)
Descriptors: MW 441.44, ALogP 6.82, HBA 2, HBD 2, PSA 57.53, QED 0.21
Compound (SMILES): N#CCC1(n2cc(-c3c(C#N)cnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3c(F)cc(C#N)cc3F)CC2)C1
InChIKey: FSKSWJIKOXAUAG-UHFFFAOYSA-N
Target: Tyrosine-protein kinase JAK1 (SINGLE PROTEIN), Homo sapiens
UniProt: P23458
Assay: In vitro JAK Kinase Assay: The catalytic domains of human JAK1 (a.a. 837-1142), Jak2 (a.a. 828-1132) and Jak3 (a.a. 781-1124) with an N-terminal His tag were expressed using baculovirus in insect cells and purified. The catalytic activity of JAK1, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by homogenous time resolved fluorescence (HTRF). IC50s of compounds were measured for each kinase in the 40 microL reactions that contain the enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. For the 1 mM IC50 measurements, ATP concentration in the reactions was 1 mM. Reactions were carried out at room temperature for 1 hr and then stopped with 20 μL 45 mM EDTA, 300 nM SA-APC, 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, Mass.). Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader (Perkin Elmer, Boston, Mass.)
Measurement: IC50 = 25 nM (pChEMBL 7.599999904632568)
Descriptors: MW 551.56, ALogP 3.68, HBA 8, HBD 1, PSA 141.42, QED 0.4
Compound (SMILES): CCC(=O)N1CCc2[nH]nc(-c3ccccc3)c2C1
InChIKey: DVIQMCGALYMKFG-UHFFFAOYSA-N
Target: Bromodomain-containing protein 4 (SINGLE PROTEIN), Homo sapiens
UniProt: O60885
Assay: Binding affinity to human His10-tagged BRD4 expressed in Escherichia coli BL21(DE3)-R3-pRARE2 using methanol by SPR assay
Measurement: Kd = 8630 nM (pChEMBL 5.059999942779541)
Descriptors: MW 255.32, ALogP 2.37, HBA 2, HBD 1, PSA 48.99, QED 0.9
Compound (SMILES): Cc1cc(COc2ccc(S(=O)(=O)NC[C@@H](C(=O)NO)N3CCN(Cc4ccc(C(F)(F)F)cc4)CC3)cc2)c2ccccc2n1
InChIKey: JCBLZSWVZUEGKV-PMERELPUSA-N
Target: Disintegrin and metalloproteinase domain-containing protein 10 (SINGLE PROTEIN), Homo sapiens
UniProt: O14672
Assay: Inhibition Assay: The molecules are dose-response tested on the following enzymes: MMP1, MMP3, MMP9, ADAM9 and ADAM10, according to the same protocol as that described for the TACE enzyme in example 28, but with different substrates (MMP R&D systems, reference: P126-990, and ADAM R&D systems, reference: ES003).
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 657.72, ALogP 4.11, HBA 8, HBD 3, PSA 124.1, QED 0.16
Compound (SMILES): Cc1cc2cc(-n3ncc(C(=O)c4cc5ccccc5[nH]4)c3N)ccc2[nH]1
InChIKey: QIASHDRGDBMNGW-UHFFFAOYSA-N
Target: Fibroblast growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P21802
Assay: Inhibition of human FGFR2 by time-resolved fluorescence or time-resolved fluorescence assay
Measurement: IC50 = 32 nM (pChEMBL 7.5)
Descriptors: MW 355.4, ALogP 3.96, HBA 4, HBD 3, PSA 92.49, QED 0.43
Compound (SMILES): CCC(=O)N1CC[C@H](Oc2ncnc3ccc(-c4cnc(OC)c(C#N)c4)cc23)C1
InChIKey: FCRWAGMUQQHCJF-KRWDZBQOSA-N
Target: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (SINGLE PROTEIN), Homo sapiens
UniProt: P48736
Assay: Inhibition of PI3K-gamma (unknown origin) by KinaseGlo assay
Measurement: IC50 = 978 nM (pChEMBL 6.010000228881836)
Descriptors: MW 403.44, ALogP 2.96, HBA 7, HBD 0, PSA 101.23, QED 0.65
Compound (SMILES): CCN1CCCC(c2nc(COc3cc4ncnc(Nc5ccc(Cl)c(Cl)c5)c4cc3OC)no2)C1
InChIKey: GCBUMMPSFVNQKY-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Inhibition of recombinant human N-terminal GST-fused KDR (D807 to V1356 residues) expressed in baculovirus infected Escherichia coli or insect Sf9 cells using poly-EY as substrate after 240 mins by luciferase coupled chemiluminescence assay
Measurement: IC50 < 50 nM (pChEMBL 7.301000118255615)
Descriptors: MW 529.43, ALogP 5.85, HBA 9, HBD 1, PSA 98.43, QED 0.3
Compound (SMILES): CCN(CC)c1ccc(-c2cc(-c3ccc(C(=O)O)cc3)ccc2OCCCCO)cc1C(C)(C)C
InChIKey: MFJSSFBKCJUROC-UHFFFAOYSA-N
Target: Retinoic acid receptor alpha (SINGLE PROTEIN), Homo sapiens
UniProt: P10276
Assay: Agonist activity at GAL4 DNA-binding domain-tagged RARalpha (unknown origin) ligand-binding domain expressed in human HG5LN cells incubated for 18 hrs by luciferase reporter gene assay
Measurement: EC50 = 180 nM (pChEMBL 6.75)
Descriptors: MW 489.66, ALogP 7.01, HBA 4, HBD 2, PSA 70, QED 0.28
Compound (SMILES): O=C(NCc1cccc(OCCCS(=O)(=O)N2CCCCC2C(=O)O)c1)c1nc2ccccc2c(=O)[nH]1
InChIKey: NEPHXSICDJEKLG-UHFFFAOYSA-N
Target: Macrophage metalloelastase (SINGLE PROTEIN), Homo sapiens
UniProt: P39900
Assay: Inhibition of recombinant human AMPA-activated MMP12 using Cy3-PLGLK(Cy5Q)AR-NH2 as substrate measured after 40 mins by spectrofluorimetric method
Measurement: IC50 = 300 nM (pChEMBL 6.519999980926514)
Descriptors: MW 528.59, ALogP 1.89, HBA 7, HBD 3, PSA 158.76, QED 0.34
Compound (SMILES): CC1c2ncn(-c3ccccn3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
InChIKey: OGZKVSNRBCPRRL-UHFFFAOYSA-N
Target: P2X purinoceptor 7 (SINGLE PROTEIN), Rattus norvegicus
UniProt: Q64663
Assay: FLIPR Assay: 1321 N1 cells expressing the recombinant human, rat or mouse P2X7 channel was cultured in HyQ DME/(HyClone/Dulbecco's Modified Eagle Medium) high glucose supplemented with 10% Fetal Bovine Serum (FBS) and appropriate selection marker. Cells were seeded at a density of 25000 cells/well (96-well clear bottom black walled plates) in 100 ul volume/well. On the day of the experiment, cell plates were washed with assay buffer, containing (in mM): 130 NaCl, 2 KCl, 1 CaCl2, 1 MgCl2, 10 HEPES, 5 glucose; pH 7.40 and 300 mOs. After the wash, cells were loaded with the Calcium-4 dye (Molecular Device) and incubated in the dark for 60 minutes. Test compounds were prepared at 250Ã¿ the test concentration in neat DMSO. Intermediate 96-well compound plates were prepared by transferring 1.2 uL of the compound into 300 uL of assay buffer. A further 3x dilution occurred when transferring 50 uL/well of the compound plate to 100 uL/well in the cell plate. Cells were incubateÂ  with test compounds and dye for 30 minutes. Calcium dye fluorescence was monitored in FLIPR as the cells were challenged by adding 50 uL/well of BzATP (final concentration is 250 uM BzATP (human and rat) or 600 (mouse)). The fluorescence change was measured 180 seconds after adding the agonist.
Measurement: IC50 = 156 nM (pChEMBL 6.809999942779541)
Descriptors: MW 420.82, ALogP 4.7, HBA 4, HBD 0, PSA 51.02, QED 0.6
Compound (SMILES): COc1cc(OC)cc(N(CCC#Cc2ccccc2)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1
InChIKey: GYBMGGFXFSFXNL-UHFFFAOYSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 489.58, ALogP 5.63, HBA 7, HBD 0, PSA 65.3, QED 0.28
Compound (SMILES): COc1cc(OC)cc(N(CC2CC2)c2ccc3ncc(-c4cnn(C(C)(C)C(=O)N5CCNCC5)c4)nc3c2)c1
InChIKey: RZRVTNNQCLYNOB-UHFFFAOYSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 = 5495.41 nM (pChEMBL 5.260000228881836)
Descriptors: MW 555.68, ALogP 4.23, HBA 9, HBD 1, PSA 97.64, QED 0.33
Compound (SMILES): COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OCc1noc(C2CCN(C)CC2)n1
InChIKey: NLASQQGOHZWAKY-UHFFFAOYSA-N
Target: Epidermal growth factor receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P00533
Assay: AlphaScreen Assay: In AlphaScreen, when the donor and acceptor beads are close in proximity, a series of photochemical events will give rise to a fluorescent signal upon light activation. Here we use biotinylated poly-(Glu, Tyr) 4:1 as the kinase substrate, streptavidin-coated donor beads and anti-phosphortyrosine antibody PY100-coated acceptor beads. Upon phosphorylation, the peptide substrate can bind to both donor and acceptor beads, thus gives rise to fluorescence. Compounds, ATP, biotinylated poly-(Glu, Tyr) and kinases are mixed in a volume of 20 μL for 1 hr at ambient temperature using Greiner 384-well white clear bottom medium binding plates. Then 10 uL solution containing 15-30 mg/mL AlphaScreen beads, 75 mM Hepes, pH 7.4, 300 mM NaCl, 120 mM EDTA, 0.3% BSA and 0.03% Tween-20 is added to each well. After 2-16 hr incubation of the beads, plates are read in a Perkin Elmer AlphaQuest reader (available from PerkinElmer Life and Analytical Sciences, Inc., of Boston Mass.).
Measurement: IC50 < 50 nM (pChEMBL 7.301000118255615)
Descriptors: MW 515.4, ALogP 5.46, HBA 9, HBD 1, PSA 98.43, QED 0.34
Compound (SMILES): Nc1ncnc2cc(CN3C(=O)CN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3C(=O)O)ccc12
InChIKey: SXJRFJQQWDUBFI-UHFFFAOYSA-N
Target: Coagulation factor X (SINGLE PROTEIN), Homo sapiens
UniProt: P00742
Assay: Biochemical assay using fluorogenic peptide substrate.Step 1: Compound transfer to plate (50 nl).Step 2: Dilute FXa in Assay Buffer.Step 3: Dilute substrate in Assay Buffer.Step 4: Add equal volumes to Assay plate (total assay volume 10 uL).Step 5: Centrifuge plate, 1 min, 1000 rpm.Step 6: Detect fluorescence signal: ex: 320 nm; Em. 405 nm (EnVision), every 10 min. 30 min pre-incubation of enzyme with compound and 15 min reaction time after substrate addition.
Measurement: IC50 = 0.642 nM (pChEMBL 9.1899995803833)
Descriptors: MW 532, ALogP 2.57, HBA 8, HBD 2, PSA 146.79, QED 0.4
Compound (SMILES): Cc1cc(C(=O)Nc2nc3cccc(C)c3n2[C@@H]2CCCCN(C(=O)/C=C/CN(C)C)C2)ccn1
InChIKey: SKLAQDNYYXAFGK-QWDXWUACSA-N
Target: Cytochrome P450 2D6 (SINGLE PROTEIN), Homo sapiens
UniProt: P10635
Assay: Inhibition of CYP2D6 (unknown origin)
Measurement: IC50 > 25000 nM (pChEMBL 4.6020002365112305)
Descriptors: MW 474.61, ALogP 3.97, HBA 6, HBD 1, PSA 83.36, QED 0.55
Compound (SMILES): CC(C)[C@@H]1c2nn(-c3cccc(S(C)(=O)=O)c3)cc2CN1c1cc(C(F)(F)F)ncn1
InChIKey: OMMCNHJJHLQJHQ-LJQANCHMSA-N
Target: Cytochrome P450 3A4 (SINGLE PROTEIN), Homo sapiens
UniProt: P08684
Assay: Inhibition of CYP3A4 (unknown origin)
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 451.47, ALogP 3.8, HBA 7, HBD 0, PSA 80.98, QED 0.6
Compound (SMILES): COc1cn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
InChIKey: MPSQYCLTAAEIDL-UHFFFAOYSA-N
Target: Plasma kallikrein (SINGLE PROTEIN), Homo sapiens
UniProt: P03952
Assay: Inhibition Assay: Test substances are dissolved in dimethyl sulphoxide and serially diluted in dimethyl sulphoxide (3000 μM to 0.0078 μM; resulting final concentrations in the test: 50 μM to 0.00013 μM). In each case 1 μl of the diluted substance solutions are placed into the wells of white microtitre plates from Greiner (384 wells). 20 μl of assay buffer (50 mM Tris/HCl pH 7.4; 100 mM sodium chloride solution; 5 mM of calcium chloride solution; 0.1% of bovine serum albumin) and 20 μl of plasma kallikrein from Kordia (0.6 nM in assay buffer) are then added successively. After 15 min of incubation, the enzyme reaction is started by addition of 20 μl of the substrate H-Pro-Phe-Arg-AMC dissolved in assay buffer (10 μl in assay buffer) from Bachem, the mixture is incubated at room temperature (22° C.) for 30 min and fluorescence is then measured (excitation: 360 nm, emission: 460 nm).
Measurement: IC50 = 17 nM (pChEMBL 7.769999980926514)
Descriptors: MW 451.87, ALogP 3.95, HBA 6, HBD 2, PSA 121.42, QED 0.58
Compound (SMILES): Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
InChIKey: OAHDIZLUMALIAR-UHFFFAOYSA-N
Target: Sodium channel protein type 5 subunit alpha (SINGLE PROTEIN), Homo sapiens
UniProt: Q14524
Assay: In Vitro Assay: HEK 293 cells stably transfected with either Nav 1.7 or with Nav 1.5 were recorded in population patch-clamp mode with the IonWorks® Quattro automated electrophysiology system in accordance with the manufacturer's specifications (Molecular Devices, LLC, Sunnyvale, Calif.). Sodium channel currents were measured in response to a train of depolarizations that induced successively greater inactivation. Cells were held at −110 mV for three seconds (Nav 1.7) or half a second (Nav 1.5) from a holding voltage of −15 mV, then put through a series of 26 pulses of 150 msec duration to −20 mV at a frequency of 5 Hz. Cells were then left unclamped for a period of 3 to 8 minutes while a single concentration of test compound was added. Cells were then reclamped and put through the same voltage protocol. Current at the end of the 26th pulse to −20 mV was subtracted from the peak current evoked by the 26th pulse to −20 mV to correct for leak current.
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 421.93, ALogP 4.44, HBA 6, HBD 1, PSA 71.53, QED 0.67
Compound (SMILES): CO[C@H]1C[C@@H](n2c(=O)n(C)c3cnc4ccc(-c5ccc(OCCCN6CCCCC6)nc5)cc4c32)C1
InChIKey: QBXNJMCSVGEQDI-ZRZAMGCNSA-N
Target: Serine/threonine-protein kinase ATR (SINGLE PROTEIN), Homo sapiens
UniProt: Q13535
Assay: Inhibition of ATR in human HT29 cells assessed as decrease in Chk1 phosphorylation at Ser 345 preincubated for 1 hr followed by 4NQO addition and measured after 1 hr by Hoechst 33342 dye-based immunofluorescence assay
Measurement: IC50 > 2600 nM (pChEMBL 5.585000038146973)
Descriptors: MW 501.63, ALogP 4.55, HBA 8, HBD 0, PSA 74.41, QED 0.33
Compound (SMILES): COc1cc(OC)cc(N(CCN2CC[C@H](C#N)C2)c2ccc3ncc(-c4cnn(C)c4)nc3c2)c1
InChIKey: NTCROAMSHNBTJA-LJQANCHMSA-N
Target: Receptor-type tyrosine-protein kinase FLT3 (SINGLE PROTEIN), Homo sapiens
UniProt: P36888
Assay: Inhibition of FLT3 (unknown origin) transfected in mouse BA/F3 cells assessed as decrease in cell proliferation in absence of mouse IL3 after 24 hrs by Alamar blue assay
Measurement: IC50 > 10000 nM (pChEMBL 5)
Descriptors: MW 483.58, ALogP 4.03, HBA 9, HBD 0, PSA 92.33, QED 0.37
Compound (SMILES): COc1cc(F)ccc1-c1nc(Nc2cccc(CS(C)(=O)=NC#N)c2)ncc1F
InChIKey: PMIUHCUGSNZOBV-UHFFFAOYSA-N
Target: Cyclin-dependent kinase 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P24941
Assay: CDK2/CycE Kinase Assay: Recombinant fusion proteins of GST and human CDK2 and of GST and human CycE, expressed in insect cells (Sf9) and purified by Glutathion-Sepharose affinity chromatography, were purchased from ProQinase GmbH (Freiburg, Germany). As substrate for the kinase reaction biotinylated peptide biotin-Ttds-YISPLKSPYKISEG (C-terminus in amid form) was used which can be purchased e.g. form the company JERINI Peptide Technologies (Berlin, Germany)For the assay 50 nl of a 100 fold concentrated solution of the test compound in DMSO was pipetted into a black low volume 384 well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2 ul of a solution of CDK2/CycE in aqueous assay buffer [50 mM Tris/HCl pH 8.0, 10 mM MgCl2, 1.0 mM dithiothreitol, 0.1 mM sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were added and the mixture was incubated for 15 min at 22 C. to allow pre-binding of the test compounds to the enzyme before the start of the kinase reaction.
Measurement: IC50 = 330 nM (pChEMBL 6.480000019073486)
Descriptors: MW 429.45, ALogP 4.25, HBA 7, HBD 1, PSA 100.26, QED 0.59
Compound (SMILES): O=C(O)C1CCN(C(=O)N2CC[C@](c3ccc(C(F)(C(F)(F)F)C(F)(F)F)cc3)(S(=O)(=O)c3ccc(F)cc3)C2)CC1
InChIKey: ZJXNCGWVVZRDGK-QHCPKHFHSA-N
Target: Oxysterols receptor LXR-beta (SINGLE PROTEIN), Homo sapiens
UniProt: P55055
Assay: Agonist activity at LXRbeta (unknown origin) expressed in African green monkey CV1 cells
Measurement: EC50 > 7500 nM (pChEMBL 5.125)
Descriptors: MW 628.54, ALogP 5.41, HBA 4, HBD 1, PSA 94.99, QED 0.35
Compound (SMILES): COc1cc(N2CCC[C@@H](O)C2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
InChIKey: ASBGJVNBZBSENK-RUZDIDTESA-N
Target: Insulin-like growth factor 1 receptor (SINGLE PROTEIN), Homo sapiens
UniProt: P08069
Assay: Inhibition of IGF1-induced human IGF1R autophosphorylation expressed in mouse NIH-3T3 cells preincubated for 2 hrs followed by IGF-1 induction measured after 15 mins by DELFIA
Measurement: IC50 < 100 nM (pChEMBL 7)
Descriptors: MW 647.69, ALogP 6.7, HBA 9, HBD 3, PSA 116.91, QED 0.17
Compound (SMILES): NCC1CCN(c2ccc(Cl)cc2NC(=O)c2cnn3cccnc23)CC1
InChIKey: ITDPQZHRPNERLI-UHFFFAOYSA-N
Target: Interleukin-1 receptor-associated kinase 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P51617
Assay: In vitro IRAK-1 and IRAK-4 Assay: Purified recombinant IRAK-4 protein was incubated with 250 uM synthetic peptide(KKARFSRFAGSSPSQSSMVAR) in 30 ul of kinase buffer including (20 mM MOPS pH7.2, 25 mM beta glycerol phosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM DTT, 50 uM ATP, 20 mM MgCl2, 10 uCi gamma-33P, 0.1% BSA) for the indicated time. For purified recombinant IRAK-1 protein kinase assay, 50 uM ATP was used. A 25 ul aliquot of the reaction mixture was transferred on to p81 phosphocellulose squares (Upstate Biotechnology, Lake Placid, N.Y.). The assay squares were washed three times with 0.75% phosphoric acid and once with acetone. Enzyme activity was measured by determining the bound radioactivity by liquid scintillation counting.
Measurement: IC50 = 920 nM (pChEMBL 6.039999961853027)
Descriptors: MW 384.87, ALogP 2.81, HBA 6, HBD 2, PSA 88.55, QED 0.72