lovingscience/chembl-v37-raw-activities huggingface dataset:
Compound (SMILES): CCC(=O)N1CCC(CC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)N[C@@H](CCC2CCNCC2)C(=O)NCc2ccc(C(=N)N)cc2)CC1
InChIKey: LWFLIRIWEPBXFX-AJQTZOPKSA-N
Target: Tissue-type plasminogen activator (SINGLE PROTEIN), Homo sapiens
UniProt: P00750
Assay: Inhibition Assay: Inhibition of human t-PA was determined by the method described in [0092]-[0098] using recombinant human tissue-type plasminogen activator (Actilyse®) from Boehringer Ingelheim at 290 U/mL and Mes-d-Cha-Gly-Arg-pNA (Pefachrome tPA) at 4 mM, 2 mM, and 1 mM as substrate; results are reported as Ki values (nanomolar).
Measurement: Ki = 5100 nM (pChEMBL 5.289999961853027)
Descriptors: MW 695.93, ALogP 2.77, HBA 7, HBD 6, PSA 186.58, QED 0.11
Compound (SMILES): CC(=O)N1CCC(CCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)N[C@@H](CCC2CCNCC2)C(=O)NCc2ccc(C(=N)N)cc2)CC1
InChIKey: QCJKXYYLKAMQSD-JHOUSYSJSA-N
Target: Plasma kallikrein (SINGLE PROTEIN), Homo sapiens
UniProt: P03952
Assay: Inhibition Assay: The inhibitory effect for the individual enzymes was determined in analogy to a previously disclosed method (Stürzebecher et al., J. Med. Chem., 40, 3091-3099 (1997)).
Measurement: Ki = 2 nM (pChEMBL 8.699999809265137)
Descriptors: MW 695.93, ALogP 2.77, HBA 7, HBD 6, PSA 186.58, QED 0.11
Compound (SMILES): N=C(N)c1ccc(CNC(=O)[C@H](CCC2CCNCC2)NC(=O)[C@@H](CCC2CCNCC2)NS(=O)(=O)Cc2ccccc2)cc1
InChIKey: ZTJVQQCXGUIYTL-XZWHSSHBSA-N
Target: Plasma kallikrein (SINGLE PROTEIN), Homo sapiens
UniProt: P03952
Assay: Inhibition Assay: Inhibition of human t-PA was determined by the method described in [0092]-[0098] using recombinant human tissue-type plasminogen activator (Actilyse®) from Boehringer Ingelheim at 290 U/mL and Mes-d-Cha-Gly-Arg-pNA (Pefachrome tPA) at 4 mM, 2 mM, and 1 mM as substrate; results are reported as Ki values (nanomolar).
Measurement: Ki > 100000 nM (pChEMBL 4)
Descriptors: MW 639.87, ALogP 2.12, HBA 7, HBD 7, PSA 178.3, QED 0.11
Compound (SMILES): COCC(=O)N1CCC(CC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)N[C@@H](CCC2CCNCC2)C(=O)NCc2ccc(C(=N)N)cc2)CC1
InChIKey: DTIUMOLBWQXRPH-AJQTZOPKSA-N
Target: Plasma kallikrein (SINGLE PROTEIN), Homo sapiens
UniProt: P03952
Assay: Inhibition Assay: Inhibition of human t-PA was determined by the method described in [0092]-[0098] using recombinant human tissue-type plasminogen activator (Actilyse®) from Boehringer Ingelheim at 290 U/mL and Mes-d-Cha-Gly-Arg-pNA (Pefachrome tPA) at 4 mM, 2 mM, and 1 mM as substrate; results are reported as Ki values (nanomolar).
Measurement: Ki > 100000 nM (pChEMBL 4)
Descriptors: MW 711.93, ALogP 2, HBA 8, HBD 6, PSA 195.81, QED 0.1
Compound (SMILES): N=C(N)c1ccc(CNC(=O)[C@H](CCC2CCNCC2)NC(=O)[C@@H](CCc2ccncc2)NS(=O)(=O)Cc2ccccc2)cc1
InChIKey: ZYKYKDNQGMXJQR-XZWHSSHBSA-N
Target: Plasma kallikrein (SINGLE PROTEIN), Homo sapiens
UniProt: P03952
Assay: Inhibition Assay: The inhibitory effect for the individual enzymes was determined in analogy to a previously disclosed method (Stürzebecher et al., J. Med. Chem., 40, 3091-3099 (1997)).
Measurement: Ki = 9 nM (pChEMBL 8.050000190734863)
Descriptors: MW 633.82, ALogP 2.37, HBA 7, HBD 6, PSA 179.16, QED 0.1
Compound (SMILES): CN(C)C(=O)N1CCC(CC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)N[C@@H](CCC2CCNCC2)C(=O)NCc2ccc(C(=N)N)cc2)CC1
InChIKey: WYOJURVOHOBMRY-AJQTZOPKSA-N
Target: Plasma kallikrein (SINGLE PROTEIN), Homo sapiens
UniProt: P03952
Assay: Inhibition Assay: The inhibitory effect for the individual enzymes was determined in analogy to a previously disclosed method (Stürzebecher et al., J. Med. Chem., 40, 3091-3099 (1997)).
Measurement: Ki = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 710.95, ALogP 2.51, HBA 7, HBD 6, PSA 189.82, QED 0.11
Compound (SMILES): CNC(=O)N1CCC(CC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)N[C@@H](CCC2CCNCC2)C(=O)NCc2ccc(C(=N)N)cc2)CC1
InChIKey: OGCGKERBEQPTBU-IOWSJCHKSA-N
Target: Tissue-type plasminogen activator (SINGLE PROTEIN), Homo sapiens
UniProt: P00750
Assay: Inhibition Assay: Inhibition of human t-PA was determined by the method described in [0092]-[0098] using recombinant human tissue-type plasminogen activator (Actilyse®) from Boehringer Ingelheim at 290 U/mL and Mes-d-Cha-Gly-Arg-pNA (Pefachrome tPA) at 4 mM, 2 mM, and 1 mM as substrate; results are reported as Ki values (nanomolar).
Measurement: Ki = 5300 nM (pChEMBL 5.28000020980835)
Descriptors: MW 696.92, ALogP 2.17, HBA 7, HBD 7, PSA 198.61, QED 0.1
Compound (SMILES): CCCC(=O)N1CCC(CC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)N[C@@H](CCC2CCNCC2)C(=O)NCc2ccc(C(=N)N)cc2)CC1
InChIKey: GWZGMZVWURNLOZ-JHOUSYSJSA-N
Target: Plasma kallikrein (SINGLE PROTEIN), Homo sapiens
UniProt: P03952
Assay: Inhibition Assay: The inhibitory effect for the individual enzymes was determined in analogy to a previously disclosed method (Stürzebecher et al., J. Med. Chem., 40, 3091-3099 (1997)).
Measurement: Ki = 2 nM (pChEMBL 8.699999809265137)
Descriptors: MW 709.96, ALogP 3.16, HBA 7, HBD 6, PSA 186.58, QED 0.1
Compound (SMILES): COC(=O)N1CCC(CC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)N[C@@H](CCC2CCNCC2)C(=O)NCc2ccc(C(=N)N)cc2)CC1
InChIKey: ZTXALZIIFRKUGE-IOWSJCHKSA-N
Target: Plasminogen (SINGLE PROTEIN), Homo sapiens
UniProt: P00747
Assay: Inhibition Assay: The inhibitory effect for the individual enzymes was determined in analogy to a previously disclosed method (Stürzebecher et al., J. Med. Chem., 40, 3091-3099 (1997)).
Measurement: Ki = 0.7 nM (pChEMBL 9.149999618530273)
Descriptors: MW 697.9, ALogP 2.6, HBA 8, HBD 6, PSA 195.81, QED 0.11
Compound (SMILES): N=C(N)c1ccc(CNC(=O)[C@H](CCC2CCNCC2)NC(=O)[C@@H](CCCc2cc[n+]([O-])cc2)NS(=O)(=O)Cc2ccccc2)cc1
InChIKey: BVZHCUOVJATBQP-IOWSJCHKSA-N
Target: Tissue-type plasminogen activator (SINGLE PROTEIN), Homo sapiens
UniProt: P00750
Assay: Inhibition Assay: Inhibition of human t-PA was determined by the method described in [0092]-[0098] using recombinant human tissue-type plasminogen activator (Actilyse®) from Boehringer Ingelheim at 290 U/mL and Mes-d-Cha-Gly-Arg-pNA (Pefachrome tPA) at 4 mM, 2 mM, and 1 mM as substrate; results are reported as Ki values (nanomolar).
Measurement: Ki = 2400 nM (pChEMBL 5.619999885559082)
Descriptors: MW 663.85, ALogP 2, HBA 7, HBD 6, PSA 193.21, QED 0.06
Compound (SMILES): CC(C)C(=O)N1CCC(CC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)N[C@@H](CCC2CCNCC2)C(=O)NCc2ccc(C(=N)N)cc2)CC1
InChIKey: RRYHCECMCWJEIU-JHOUSYSJSA-N
Target: Plasminogen (SINGLE PROTEIN), Homo sapiens
UniProt: P00747
Assay: Inhibition Assay: The inhibitory effect for the individual enzymes was determined in analogy to a previously disclosed method (Stürzebecher et al., J. Med. Chem., 40, 3091-3099 (1997)).
Measurement: Ki = 0.6 nM (pChEMBL 9.220000267028809)
Descriptors: MW 709.96, ALogP 3.01, HBA 7, HBD 6, PSA 186.58, QED 0.11
Compound (SMILES): N=C(N)c1ccc(CNC(=O)[C@H](CCC2CCNCC2)NC(=O)[C@@H](CCCc2ccccc2)NS(=O)(=O)Cc2ccccc2)cc1
InChIKey: MCDKKKIUEGNSPK-AJQTZOPKSA-N
Target: Plasminogen (SINGLE PROTEIN), Homo sapiens
UniProt: P00747
Assay: Inhibition Assay: The inhibitory effect for the individual enzymes was determined in analogy to a previously disclosed method (Stürzebecher et al., J. Med. Chem., 40, 3091-3099 (1997)).
Measurement: Ki = 0.25 nM (pChEMBL 9.600000381469727)
Descriptors: MW 646.86, ALogP 3.36, HBA 6, HBD 6, PSA 166.27, QED 0.1
Compound (SMILES): N=C(N)c1ccc(CNC(=O)[C@H](CCC2CCNCC2)NC(=O)[C@H](NS(=O)(=O)Cc2ccccc2)c2ccccc2)cc1
InChIKey: BQJXMSPBOZFQJJ-URLMMPGGSA-N
Target: Vitamin K-dependent protein C (SINGLE PROTEIN), Homo sapiens
UniProt: P04070
Assay: Inhibition Assay: Inhibition of human aPC was determined by the method described in [0092]-[0098] using human activated protein C from Enzyme Research Laboratories at 2.2 nM and H-D-Lys(Cbo)-Pro-Arg-pNA (Pefachrome PCa) at 2 mM, 1 mM, and 0.5 mM as substrate; results are reported as Ki values (nanomolar).
Measurement: Ki = 210 nM (pChEMBL 6.679999828338623)
Descriptors: MW 604.78, ALogP 2.71, HBA 6, HBD 6, PSA 166.27, QED 0.12
Compound (SMILES): N=C(N)c1ccc(CNC(=O)[C@H](CCC2CCNCC2)NC(=O)[C@@H](CCc2cc[n+]([O-])cc2)NS(=O)(=O)Cc2ccccc2)cc1
InChIKey: DXGZDORACWBTJS-XZWHSSHBSA-N
Target: Plasma kallikrein (SINGLE PROTEIN), Homo sapiens
UniProt: P03952
Assay: Inhibition Assay: The inhibitory effect for the individual enzymes was determined in analogy to a previously disclosed method (Stürzebecher et al., J. Med. Chem., 40, 3091-3099 (1997)).
Measurement: Ki = 20 nM (pChEMBL 7.699999809265137)
Descriptors: MW 649.82, ALogP 1.61, HBA 7, HBD 6, PSA 193.21, QED 0.06
Compound (SMILES): COC(=O)N1CCC(CCC[C@@H](NS(=O)(=O)Cc2ccccc2)C(=O)N[C@@H](CCC2CCNCC2)C(=O)NCc2ccc(C(=N)N)cc2)CC1
InChIKey: BJSIWIFJSRFHPS-AJQTZOPKSA-N
Target: Plasminogen (SINGLE PROTEIN), Homo sapiens
UniProt: P00747
Assay: Inhibition Assay: The inhibitory effect for the individual enzymes was determined in analogy to a previously disclosed method (Stürzebecher et al., J. Med. Chem., 40, 3091-3099 (1997)).
Measurement: Ki = 1 nM (pChEMBL 9)
Descriptors: MW 711.93, ALogP 2.99, HBA 8, HBD 6, PSA 195.81, QED 0.11
Compound (SMILES): COC(=O)c1cccc(CS(=O)(=O)N[C@H](CCCc2ccccc2)C(=O)N[C@@H](CCC2CCNCC2)C(=O)NCc2ccc(C(=N)N)cc2)c1
InChIKey: JPGNXUNXIAMWMQ-JHOUSYSJSA-N
Target: Transcription initiation factor IIA subunit 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P52655
Assay: Inhibition Assay: Inhibition of human t-PA was determined by the method described in [0092]-[0098] using recombinant human tissue-type plasminogen activator (Actilyse®) from Boehringer Ingelheim at 290 U/mL and Mes-d-Cha-Gly-Arg-pNA (Pefachrome tPA) at 4 mM, 2 mM, and 1 mM as substrate; results are reported as Ki values (nanomolar).
Measurement: Ki = 920 nM (pChEMBL 6.039999961853027)
Descriptors: MW 704.89, ALogP 3.15, HBA 8, HBD 6, PSA 192.57, QED 0.07
Compound (SMILES): N=C(N)c1ccc(CNC(=O)[C@H](CCC2CCNCC2)NC(=O)[C@@H](CCCc2ccncc2)NS(=O)(=O)Cc2ccccc2)cc1
InChIKey: VNKFZBCCJJVXJG-IOWSJCHKSA-N
Target: Plasma kallikrein (SINGLE PROTEIN), Homo sapiens
UniProt: P03952
Assay: Inhibition Assay: Inhibition of human t-PA was determined by the method described in [0092]-[0098] using recombinant human tissue-type plasminogen activator (Actilyse®) from Boehringer Ingelheim at 290 U/mL and Mes-d-Cha-Gly-Arg-pNA (Pefachrome tPA) at 4 mM, 2 mM, and 1 mM as substrate; results are reported as Ki values (nanomolar).
Measurement: Ki > 80000 nM (pChEMBL 4.0970001220703125)
Descriptors: MW 647.85, ALogP 2.76, HBA 7, HBD 6, PSA 179.16, QED 0.1
Compound (SMILES): N=C(N)c1ccc(CNC(=O)[C@H](CCC2CCNCC2)NC(=O)[C@@H](CCCn2cnnn2)NS(=O)(=O)Cc2ccccc2)cc1
InChIKey: RUUQARAMINJWGP-RRPNLBNLSA-N
Target: Plasminogen (SINGLE PROTEIN), Homo sapiens
UniProt: P00747
Assay: Inhibition Assay: The inhibitory effect for the individual enzymes was determined in analogy to a previously disclosed method (Stürzebecher et al., J. Med. Chem., 40, 3091-3099 (1997)).
Measurement: Ki = 8 nM (pChEMBL 8.100000381469727)
Descriptors: MW 638.8, ALogP 0.81, HBA 10, HBD 6, PSA 209.87, QED 0.09
Compound (SMILES): O=C(Nc1cccc(Cl)c1)c1cc(Oc2cccnc2)ccn1
InChIKey: BLIMSXQCXUBYGP-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P31424
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 = 358 nM (pChEMBL 6.449999809265137)
Descriptors: MW 325.75, ALogP 4.17, HBA 4, HBD 1, PSA 64.11, QED 0.78
Compound (SMILES): Cc1csc(NC(=O)c2cc(Oc3cccnc3)ccn2)n1
InChIKey: KFIGFLNMPKDABO-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P41594
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 = 101 nM (pChEMBL 7)
Descriptors: MW 312.35, ALogP 3.29, HBA 6, HBD 1, PSA 77, QED 0.8
Compound (SMILES): Cc1csc(NC(=O)c2cncc(Oc3cccnc3)c2)n1
InChIKey: MWZNQRPRJKAROY-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P41594
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 = 2160 nM (pChEMBL 5.670000076293945)
Descriptors: MW 312.35, ALogP 3.29, HBA 6, HBD 1, PSA 77, QED 0.8
Compound (SMILES): Cc1csc(NC(=O)c2cc(Oc3cncnc3)ccn2)n1
InChIKey: HQSAJPPYHDESIU-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P31424
Assay: Negative allosteric modulation of rat mGlu5 receptor expressed in HEK293A cells assessed as inhibition of glutamate induced-calcium mobilization preincubated for 2.3 mins followed by glutamate addition measured after 1.9 mins by Fluo-4 AM dye based fluorescence assay
Measurement: IC50 = 200 nM (pChEMBL 6.699999809265137)
Descriptors: MW 313.34, ALogP 2.68, HBA 7, HBD 1, PSA 89.89, QED 0.8
Compound (SMILES): Cc1csc(NC(=O)c2cc(N(C)c3cncnc3)ccn2)n1
InChIKey: ICCLINKATILEGF-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P31424
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 = 1930 nM (pChEMBL 5.710000038146973)
Descriptors: MW 326.39, ALogP 2.66, HBA 7, HBD 1, PSA 83.9, QED 0.79
Compound (SMILES): Cc1cccc(NC(=O)c2cc(N(C)c3cncnc3)ccn2)n1
InChIKey: ZVRKZIBPVUEXBY-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P41594
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 = 2150 nM (pChEMBL 5.670000076293945)
Descriptors: MW 320.36, ALogP 2.6, HBA 6, HBD 1, PSA 83.9, QED 0.8
Compound (SMILES): O=C(Nc1ccccn1)c1cc(Oc2cncnc2)ccn1
InChIKey: FELLWSPKJLIKKD-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P31424
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 = 114 nM (pChEMBL 6.940000057220459)
Descriptors: MW 293.29, ALogP 2.31, HBA 6, HBD 1, PSA 89.89, QED 0.79
Compound (SMILES): Cc1cccc(NC(=O)c2cc(Oc3cncnc3)ccn2)n1
InChIKey: MQJNIJYRBOZJEB-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P31424
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 = 56 nM (pChEMBL 7.25)
Descriptors: MW 307.31, ALogP 2.62, HBA 6, HBD 1, PSA 89.89, QED 0.8
Compound (SMILES): O=C(Nc1ccc(F)cn1)c1cc(Oc2cncnc2)ccn1
InChIKey: VJCZZCNDIYFAPL-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P31424
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 = 389 nM (pChEMBL 6.409999847412109)
Descriptors: MW 311.28, ALogP 2.45, HBA 6, HBD 1, PSA 89.89, QED 0.8
Compound (SMILES): O=C(Nc1cccc(Cl)n1)c1cc(Oc2cncnc2)ccn1
InChIKey: UMYHTSFSQDURMB-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P41594
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 = 245 nM (pChEMBL 6.610000133514404)
Descriptors: MW 327.73, ALogP 2.96, HBA 6, HBD 1, PSA 89.89, QED 0.74
Compound (SMILES): O=C(NC1CCCCCC1)c1cc(Oc2cncnc2)ccn1
InChIKey: DJJCAFFBYJWYOB-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P31424
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 > 30000 nM (pChEMBL 4.5229997634887695)
Descriptors: MW 312.37, ALogP 3.12, HBA 5, HBD 1, PSA 77, QED 0.88
Compound (SMILES): O=C(Nc1cc(F)ccn1)c1cc(Oc2cncnc2)ccn1
InChIKey: FXBAUBWMBYTCIL-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Homo sapiens
UniProt: P41594
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 = 201 nM (pChEMBL 6.699999809265137)
Descriptors: MW 311.28, ALogP 2.45, HBA 6, HBD 1, PSA 89.89, QED 0.8
Compound (SMILES): O=C(Nc1cccc(F)n1)c1cc(Oc2cncnc2)ccn1
InChIKey: GGFLPDBSANBACY-UHFFFAOYSA-N
Target: Metabotropic glutamate receptor 5 (SINGLE PROTEIN), Rattus norvegicus
UniProt: P31424
Assay: Cell Based Assay: mGluR5 activity was determined in a cell-based assay.
Measurement: IC50 = 128 nM (pChEMBL 6.889999866485596)
Descriptors: MW 311.28, ALogP 2.45, HBA 6, HBD 1, PSA 89.89, QED 0.74
Compound (SMILES): Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NO)c[nH]4)c3)cc2)c1
InChIKey: JYJKNIHQZXCKPB-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P17948
Assay: Kinase assays: Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30.mu.g of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction. Reactions were carried out in 120.mu.L reaction volumes containing 3.6.mu.M ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM Na.sub.3 VO.sub.4). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 0.5 ng of purified protein. Following a ten minute incubation at 25.degree. C., the reactions were washed four times with PBS containing 0.05% Tween-20. 100.mu.l of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate was diluted 1:10000 in PBS-Tween-20 and added to the wells for 30 minutes.
Measurement: IC50 = 13 nM (pChEMBL 7.889999866485596)
Descriptors: MW 461.45, ALogP 5.08, HBA 5, HBD 5, PSA 128.37, QED 0.2
Compound (SMILES): Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCO)c[nH]4)c3)cc2)c1
InChIKey: IHGRRQDGJVUJSZ-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Kinase assays: Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30.mu.g of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction. Reactions were carried out in 120.mu.L reaction volumes containing 3.6.mu.M ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM Na.sub.3 VO.sub.4). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 0.5 ng of purified protein. Following a ten minute incubation at 25.degree. C., the reactions were washed four times with PBS containing 0.05% Tween-20. 100.mu.l of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate was diluted 1:10000 in PBS-Tween-20 and added to the wells for 30 minutes.
Measurement: IC50 = 38 nM (pChEMBL 7.420000076293945)
Descriptors: MW 503.53, ALogP 5.07, HBA 5, HBD 5, PSA 128.37, QED 0.2
Compound (SMILES): Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
InChIKey: PTUJZMRANLZUJP-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P17948
Assay: Kinase assays: Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30.mu.g of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction. Reactions were carried out in 120.mu.L reaction volumes containing 3.6.mu.M ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM Na.sub.3 VO.sub.4). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 0.5 ng of purified protein. Following a ten minute incubation at 25.degree. C., the reactions were washed four times with PBS containing 0.05% Tween-20. 100.mu.l of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate was diluted 1:10000 in PBS-Tween-20 and added to the wells for 30 minutes.
Measurement: IC50 = 2 nM (pChEMBL 8.699999809265137)
Descriptors: MW 428.45, ALogP 5.52, HBA 4, HBD 4, PSA 116.34, QED 0.32
Compound (SMILES): O=C(Nc1ccc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
InChIKey: QLJWNTHEJPFKDE-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Kinase assays: Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30.mu.g of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction. Reactions were carried out in 120.mu.L reaction volumes containing 3.6.mu.M ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM Na.sub.3 VO.sub.4). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 0.5 ng of purified protein. Following a ten minute incubation at 25.degree. C., the reactions were washed four times with PBS containing 0.05% Tween-20. 100.mu.l of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate was diluted 1:10000 in PBS-Tween-20 and added to the wells for 30 minutes.
Measurement: IC50 = 14 nM (pChEMBL 7.849999904632568)
Descriptors: MW 516.86, ALogP 6.88, HBA 4, HBD 4, PSA 116.34, QED 0.22
Compound (SMILES): Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)OCC(O)CO)c[nH]4)c3)cc2)c1
InChIKey: QHWJRQVVIZMMLO-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 2 (SINGLE PROTEIN), Homo sapiens
UniProt: P35968
Assay: Kinase assays: Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30.mu.g of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction. Reactions were carried out in 120.mu.L reaction volumes containing 3.6.mu.M ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM Na.sub.3 VO.sub.4). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 0.5 ng of purified protein. Following a ten minute incubation at 25.degree. C., the reactions were washed four times with PBS containing 0.05% Tween-20. 100.mu.l of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate was diluted 1:10000 in PBS-Tween-20 and added to the wells for 30 minutes.
Measurement: IC50 = 43 nM (pChEMBL 7.369999885559082)
Descriptors: MW 520.52, ALogP 4.47, HBA 7, HBD 5, PSA 145.8, QED 0.2
Compound (SMILES): Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
InChIKey: BDTDDTOUVUTYCH-UHFFFAOYSA-N
Target: Vascular endothelial growth factor receptor 1 (SINGLE PROTEIN), Homo sapiens
UniProt: P17948
Assay: Kinase assays: Kinase assays were performed in 96 well microtiter plates that were coated overnight with 30.mu.g of poly-Glu-Tyr (4:1) in 10 mM Phosphate Buffered Saline (PBS), pH 7.2-7.4. The plates were incubated with 1% BSA and then washed four times with PBS prior to starting the reaction. Reactions were carried out in 120.mu.L reaction volumes containing 3.6.mu.M ATP in kinase buffer (50 mM Hepes buffer pH 7.4, 20 mM MgCl.sub.2, 0.1 mM MnCl.sub.2 and 0.2 mM Na.sub.3 VO.sub.4). Test compounds were reconstituted in 100% DMSO and added to the reaction to give a final DMSO concentration of 5%. Reactions were initiated by the addition 0.5 ng of purified protein. Following a ten minute incubation at 25.degree. C., the reactions were washed four times with PBS containing 0.05% Tween-20. 100.mu.l of a monoclonal anti-phosphotyrosine antibody-peroxidase conjugate was diluted 1:10000 in PBS-Tween-20 and added to the wells for 30 minutes.
Measurement: IC50 = 4 nM (pChEMBL 8.399999618530273)
Descriptors: MW 446.44, ALogP 5.66, HBA 4, HBD 4, PSA 116.34, QED 0.31
Compound (SMILES): O=Cc1cc(-c2cccs2)cc([N+](=O)[O-])c1O
InChIKey: RZMOISAIMNJGKK-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 42 nM (pChEMBL 7.380000114440918)
Descriptors: MW 249.25, ALogP 2.84, HBA 5, HBD 1, PSA 80.44, QED 0.51
Compound (SMILES): O=Cc1cc(-c2cccs2)cc(F)c1O
InChIKey: ZODKJLYQIFWFAO-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 40 nM (pChEMBL 7.400000095367432)
Descriptors: MW 222.24, ALogP 3.07, HBA 3, HBD 1, PSA 37.3, QED 0.79
Compound (SMILES): O=Cc1cc(-c2cncnc2)cc(F)c1O
InChIKey: DQDRCSMEJUSNKC-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 79 nM (pChEMBL 7.099999904632568)
Descriptors: MW 218.19, ALogP 1.8, HBA 4, HBD 1, PSA 63.08, QED 0.78
Compound (SMILES): O=Cc1cc(-c2cccs2)ccc1O
InChIKey: JDXKZIUDWWNBDM-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 80 nM (pChEMBL 7.099999904632568)
Descriptors: MW 204.25, ALogP 2.93, HBA 3, HBD 1, PSA 37.3, QED 0.76
Compound (SMILES): COc1cc(-c2cccc(C(=O)O)c2)cc(C=O)c1O
InChIKey: WKVDZYNPTGFSGI-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 102 nM (pChEMBL 6.989999771118164)
Descriptors: MW 272.26, ALogP 2.58, HBA 4, HBD 2, PSA 83.83, QED 0.84
Compound (SMILES): COc1cc(-c2cccs2)cc(C=O)c1O
InChIKey: GFWTZJWQECNYSN-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 22 nM (pChEMBL 7.659999847412109)
Descriptors: MW 234.28, ALogP 2.94, HBA 4, HBD 1, PSA 46.53, QED 0.83
Compound (SMILES): COc1cc(-c2cnn(C)c2)cc(C=O)c1O
InChIKey: DZRMTPIBKMPBGX-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 772 nM (pChEMBL 6.110000133514404)
Descriptors: MW 232.24, ALogP 1.61, HBA 5, HBD 1, PSA 64.35, QED 0.82
Compound (SMILES): COc1cc(-c2ccc3c(c2)CCO3)cc(C=O)c1O
InChIKey: QPACVKDAIWVNGH-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 143 nM (pChEMBL 6.840000152587891)
Descriptors: MW 270.28, ALogP 2.82, HBA 4, HBD 1, PSA 55.76, QED 0.87
Compound (SMILES): COc1cc(-c2ccncc2)cc(C=O)c1O
InChIKey: HAODQXIJMBNKBB-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 580 nM (pChEMBL 6.239999771118164)
Descriptors: MW 229.24, ALogP 2.28, HBA 4, HBD 1, PSA 59.42, QED 0.82
Compound (SMILES): COc1ccc(-c2ccncc2)c(C=O)c1O
InChIKey: CYNABUBZNGLJBG-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 17710 nM (pChEMBL 4.75)
Descriptors: MW 229.24, ALogP 2.28, HBA 4, HBD 1, PSA 59.42, QED 0.82
Compound (SMILES): O=Cc1c(-c2cncnc2)ccc(C(=O)O)c1O
InChIKey: MOOVOTIHKMKJQQ-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 > 20000 nM (pChEMBL 4.698999881744385)
Descriptors: MW 244.21, ALogP 1.36, HBA 5, HBD 2, PSA 100.38, QED 0.79
Compound (SMILES): O=Cc1cc(-c2ccncc2)ccc1O
InChIKey: AWOHFBHWSKCQFQ-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 80000 nM (pChEMBL 4.099999904632568)
Descriptors: MW 199.21, ALogP 2.27, HBA 3, HBD 1, PSA 50.19, QED 0.75
Compound (SMILES): O=Cc1cc(-c2cccnc2)cc(F)c1O
InChIKey: NVTGSOKDKHGFDY-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assays: IRE-1 alpha, T1 RNase, and RNase A assays carried out in vitro with several o-vanillin derivatives to demonstrate selectivity of the derivatives for IRE-1 alpha. T1 RNase was assayed as follows. Five ul of a reaction mixture comprising 1x reaction buffer (5x reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three ul of a 1/48,000 dilution of an approximately 200,000 U/ml RNase T1 (Worthington) preparation were added to each test well and to positive control wells (final concentration 49.5 pg/well). Negative control wells contained only reaction mixture and test compound. After spinning the plates at 1200 rpm for 30 seconds, 3 ul of the mini-XBP-1 mRNA stem-loop substrate described in Example 1 were added to each well of a control plate.
Measurement: IC50 = 163 nM (pChEMBL 6.789999961853027)
Descriptors: MW 217.2, ALogP 2.41, HBA 3, HBD 1, PSA 50.19, QED 0.79
Compound (SMILES): COc1cc(-c2cccnc2)cc(C=O)c1O
InChIKey: RXRLTYDBSJJXMV-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 30000 nM (pChEMBL 4.519999980926514)
Descriptors: MW 229.24, ALogP 2.28, HBA 4, HBD 1, PSA 59.42, QED 0.82
Compound (SMILES): COc1cc(-c2ccc(C)s2)cc(C=O)c1O
InChIKey: MSVPDYYUKAKQHT-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 50000 nM (pChEMBL 4.300000190734863)
Descriptors: MW 248.3, ALogP 3.25, HBA 4, HBD 1, PSA 46.53, QED 0.85
Compound (SMILES): COc1ccc(-c2cc(F)c(O)c(C=O)c2)cn1
InChIKey: OIWKSWFIEZSKTK-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 80000 nM (pChEMBL 4.099999904632568)
Descriptors: MW 247.22, ALogP 2.41, HBA 4, HBD 1, PSA 59.42, QED 0.85
Compound (SMILES): COc1cc(-c2ccc(C(C)=O)s2)cc(C=O)c1O
InChIKey: RMXHEBAUEAQDLH-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 30000 nM (pChEMBL 4.519999980926514)
Descriptors: MW 276.31, ALogP 3.14, HBA 5, HBD 1, PSA 63.6, QED 0.69
Compound (SMILES): COc1ccc(-c2cc(C=O)c(O)c([N+](=O)[O-])c2)cn1
InChIKey: NXRTXJYJMPSCBE-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 70000 nM (pChEMBL 4.159999847412109)
Descriptors: MW 274.23, ALogP 2.18, HBA 6, HBD 1, PSA 102.56, QED 0.52
Compound (SMILES): COc1cc(-c2cccc3ncccc23)cc(C=O)c1O
InChIKey: RCLLQACBAVZRCV-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 70000 nM (pChEMBL 4.159999847412109)
Descriptors: MW 279.3, ALogP 3.43, HBA 4, HBD 1, PSA 59.42, QED 0.75
Compound (SMILES): O=Cc1cc(-c2cccc3ncccc23)cc(F)c1O
InChIKey: SUGJWLFOIBWGSP-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: Cell-Based Assay: Initial cell-based XBP-1 mRNA splicing assays confirmed IRE-1α inhibition with several potent 5-bromo and 6 bromo o-vanillins. HEK293 cells were incubated with compound either overnight or for 2 hours prior to IRE-1α activation with the UPR inducing reagent thapsigargin. IRE-1α mediated XBP-1 splicing was measured by RT-PCR using XBP-1 specific primers flanking the 26 bp intron excised by IRE-1α. The results are shown in FIG. 1. It can be observed that at the higher concentrations, there is relatively more of the unspliced XBP-1 (upper band: substrate) compared to the spliced form (lower band: product).
Measurement: EC50 = 80000 nM (pChEMBL 4.099999904632568)
Descriptors: MW 267.26, ALogP 3.56, HBA 3, HBD 1, PSA 50.19, QED 0.72
Compound (SMILES): O=Cc1cc(-c2cccc3ncccc23)cc([N+](=O)[O-])c1O
InChIKey: LFFOXNMZCQIGTC-UHFFFAOYSA-N
Target: Serine/threonine-protein kinase/endoribonuclease IRE1 (SINGLE PROTEIN), Homo sapiens
UniProt: O75460
Assay: In Vitro Enzyme Assay: A fusion protein comprising glutathione S transferase (GST) and human IRE-1α (GST-IRE-1α) was obtained from a 500 ml baculovirus-infected insect cell culture and used to measure IRE-1α activity in vitro. Five μl of a reaction mixture comprising 1× reaction buffer (5× reaction buffer is 100 mM Hepes pH 7.5, 250 mM KOAc, 2.5 mM MgCl2), 3 mM DTT, and 0.4% polyethylene glycol water were added to each well of 384 well plates. Twenty-five nanoliters of a 1 mM test compound solution were added to test wells. Three μl of a 128 ng/ml IRE-1α preparation were added to each test well and to positive control wells (final concentration 5.82 ng/well). Negative control wells contained only reaction mixture and test compound.After spinning the plates at 1200 rpm for 30 seconds, 3 μl of an IRE-1α human mini-XBP-1 mRNA stem-loop substrate 5′-CAGUCCGCAGCACUG-3′ (SEQ ID NO:1), labeled with the fluorescent dye Cy5 at the 5′ end and Black Hole Quench
Measurement: IC50 = 333 nM (pChEMBL 6.480000019073486)
Descriptors: MW 294.27, ALogP 3.33, HBA 5, HBD 1, PSA 93.33, QED 0.45