|
Displacement of fluorescein labeled BAD peptide from Bcl-XL by fluorescence polarization assay
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins.
Year : 2008
Volume : 51
Issue : 21
First Page : 6902
Last Page : 6915
Authors : Park CM, Bruncko M, Adickes J, Bauch J, Ding H, Kunzer A, Marsh KC, Nimmer P, Shoemaker AR, Song X, Tahir SK, Tse C, Wang X, Wendt MD, Yang X, Zhang H, Fesik SW, Rosenberg SH, Elmore SW.
Abstract : Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC 50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.
|
Displacement of fluorescein labeled Bax peptide from Bcl2 by fluorescence polarization assay
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins.
Year : 2008
Volume : 51
Issue : 21
First Page : 6902
Last Page : 6915
Authors : Park CM, Bruncko M, Adickes J, Bauch J, Ding H, Kunzer A, Marsh KC, Nimmer P, Shoemaker AR, Song X, Tahir SK, Tse C, Wang X, Wendt MD, Yang X, Zhang H, Fesik SW, Rosenberg SH, Elmore SW.
Abstract : Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC 50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.
|
Cytotoxicity against IL3-dependent mouse FL5.12 cells overexpressing human Bcl2 assessed as cell viability after 24 hrs by MTS assay in absence of serum
|
Mus musculus
|
5.9
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins.
Year : 2008
Volume : 51
Issue : 21
First Page : 6902
Last Page : 6915
Authors : Park CM, Bruncko M, Adickes J, Bauch J, Ding H, Kunzer A, Marsh KC, Nimmer P, Shoemaker AR, Song X, Tahir SK, Tse C, Wang X, Wendt MD, Yang X, Zhang H, Fesik SW, Rosenberg SH, Elmore SW.
Abstract : Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC 50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.
|
Cytotoxicity against IL3-dependent mouse FL5.12 cells overexpressing human Bcl-XL assessed as cell viability after 24 hrs by MTS assay in absence of serum
|
Mus musculus
|
4.2
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins.
Year : 2008
Volume : 51
Issue : 21
First Page : 6902
Last Page : 6915
Authors : Park CM, Bruncko M, Adickes J, Bauch J, Ding H, Kunzer A, Marsh KC, Nimmer P, Shoemaker AR, Song X, Tahir SK, Tse C, Wang X, Wendt MD, Yang X, Zhang H, Fesik SW, Rosenberg SH, Elmore SW.
Abstract : Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC 50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.
|
Cytotoxicity against human NCI-H146 cells assessed as cell viability after 48 hrs in presence of 10% human serum
|
Homo sapiens
|
86.7
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins.
Year : 2008
Volume : 51
Issue : 21
First Page : 6902
Last Page : 6915
Authors : Park CM, Bruncko M, Adickes J, Bauch J, Ding H, Kunzer A, Marsh KC, Nimmer P, Shoemaker AR, Song X, Tahir SK, Tse C, Wang X, Wendt MD, Yang X, Zhang H, Fesik SW, Rosenberg SH, Elmore SW.
Abstract : Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC 50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.
|
Binding affinity to BH3 binding groove of BclXL
|
None
|
0.5
nM
|
|
Journal : J. Med. Chem.
Title : Recent developments in fragment-based drug discovery.
Year : 2008
Volume : 51
Issue : 13
First Page : 3661
Last Page : 3680
Authors : Congreve M, Chessari G, Tisi D, Woodhead AJ.
|
Binding affinity to Bcl-xL by competitive fluorescence polarization assay
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Fragment-based deconstruction of Bcl-xL inhibitors.
Year : 2010
Volume : 53
Issue : 6
First Page : 2577
Last Page : 2588
Authors : Barelier S, Pons J, Marcillat O, Lancelin JM, Krimm I.
Abstract : Fragment-based drug design consists of screening low-molecular-weight compounds in order to identify low-affinity ligands that are then modified or linked to yield potent inhibitors. The method thus attempts to build bioactive molecules in a modular way and relies on the hypothesis that the fragment binding mode will be conserved upon elaboration of the active molecule. If the inverse process is considered, do the fragments resulting from the deconstruction of high-affinity inhibitors recapitulate their binding mode in the large molecule? Few studies deal with this issue. Here, we report the analysis of 22 fragments resulting from the dissection of 9 inhibitors of the antiapoptotic protein Bcl-x(L). To determine if the fragments retained affinity toward the protein and identify their binding site, ligand-observed and protein-observed NMR experiments were used. The analysis of the fragments behavior illustrates the complexity of low-affinity protein-ligand interactions involved in the fragment-based construction of bioactive molecules.
|
Binding affinity to Bcl-xl
|
None
|
36.0
nM
|
|
Journal : J. Med. Chem.
Title : Toward the development of innovative bifunctional agents to induce differentiation and to promote apoptosis in leukemia: clinical candidates and perspectives.
Year : 2010
Volume : 53
Issue : 19
First Page : 6779
Last Page : 6810
Authors : Vizirianakis IS, Chatzopoulou M, Bonovolias ID, Nicolaou I, Demopoulos VJ, Tsiftsoglou AS.
|
Cytotoxicity against human NCI-H146 after 48 hrs by MTS assay in presence of 10% human serum
|
Homo sapiens
|
80.0
nM
|
|
Journal : J. Med. Chem.
Title : Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity.
Year : 2011
Volume : 54
Issue : 6
First Page : 1914
Last Page : 1926
Authors : Sleebs BE, Czabotar PE, Fairbrother WJ, Fairlie WD, Flygare JA, Huang DC, Kersten WJ, Koehler MF, Lessene G, Lowes K, Parisot JP, Smith BJ, Smith ML, Souers AJ, Street IP, Yang H, Baell JB.
Abstract : ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-x(L) and Bcl-2. This class of putative anticancer agents invariantly contains an acylsulfonamide core. We have designed and synthesized a series of novel quinazoline-based inhibitors of Bcl-2 and Bcl-x(L) that contain a heterocyclic alternative to the acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines in the presence of 10% human serum. This comprises the first successful demonstration of a quinazoline sulfonamide core serving as an effective benzoylsulfonamide bioisostere. Additionally, these novel quinazolines comprise only the second known class of Bcl-2 family protein inhibitors to induce mechanism-based cell death.
|
Cytotoxicity against human NCI-H889 after 48 hrs by MTS assay in presence of 10% human serum
|
Homo sapiens
|
120.0
nM
|
|
Journal : J. Med. Chem.
Title : Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity.
Year : 2011
Volume : 54
Issue : 6
First Page : 1914
Last Page : 1926
Authors : Sleebs BE, Czabotar PE, Fairbrother WJ, Fairlie WD, Flygare JA, Huang DC, Kersten WJ, Koehler MF, Lessene G, Lowes K, Parisot JP, Smith BJ, Smith ML, Souers AJ, Street IP, Yang H, Baell JB.
Abstract : ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-x(L) and Bcl-2. This class of putative anticancer agents invariantly contains an acylsulfonamide core. We have designed and synthesized a series of novel quinazoline-based inhibitors of Bcl-2 and Bcl-x(L) that contain a heterocyclic alternative to the acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines in the presence of 10% human serum. This comprises the first successful demonstration of a quinazoline sulfonamide core serving as an effective benzoylsulfonamide bioisostere. Additionally, these novel quinazolines comprise only the second known class of Bcl-2 family protein inhibitors to induce mechanism-based cell death.
|
Cytotoxicity against human NCI-H1963 after 48 hrs by MTS assay in presence of 10% human serum
|
Homo sapiens
|
51.0
nM
|
|
Journal : J. Med. Chem.
Title : Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity.
Year : 2011
Volume : 54
Issue : 6
First Page : 1914
Last Page : 1926
Authors : Sleebs BE, Czabotar PE, Fairbrother WJ, Fairlie WD, Flygare JA, Huang DC, Kersten WJ, Koehler MF, Lessene G, Lowes K, Parisot JP, Smith BJ, Smith ML, Souers AJ, Street IP, Yang H, Baell JB.
Abstract : ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-x(L) and Bcl-2. This class of putative anticancer agents invariantly contains an acylsulfonamide core. We have designed and synthesized a series of novel quinazoline-based inhibitors of Bcl-2 and Bcl-x(L) that contain a heterocyclic alternative to the acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines in the presence of 10% human serum. This comprises the first successful demonstration of a quinazoline sulfonamide core serving as an effective benzoylsulfonamide bioisostere. Additionally, these novel quinazolines comprise only the second known class of Bcl-2 family protein inhibitors to induce mechanism-based cell death.
|
Cytotoxicity against human NCI-H1417 cells assessed as growth inhibition after 4 days by WST assay
|
Homo sapiens
|
54.2
nM
|
|
Journal : J. Med. Chem.
Title : A potent and highly efficacious Bcl-2/Bcl-xL inhibitor.
Year : 2013
Volume : 56
Issue : 7
First Page : 3048
Last Page : 3067
Authors : Aguilar A, Zhou H, Chen J, Liu L, Bai L, McEachern D, Yang CY, Meagher J, Stuckey J, Wang S.
Abstract : Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with K(i) values of <1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete, and durable tumor regression in vivo at a well-tolerated dose schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.
|
Cytotoxicity against human NCI-H187 cells assessed as growth inhibition after 4 days by WST assay
|
Homo sapiens
|
38.4
nM
|
|
Journal : J. Med. Chem.
Title : A potent and highly efficacious Bcl-2/Bcl-xL inhibitor.
Year : 2013
Volume : 56
Issue : 7
First Page : 3048
Last Page : 3067
Authors : Aguilar A, Zhou H, Chen J, Liu L, Bai L, McEachern D, Yang CY, Meagher J, Stuckey J, Wang S.
Abstract : Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with K(i) values of <1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete, and durable tumor regression in vivo at a well-tolerated dose schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.
|
Cytotoxicity against human NCI-H1963 cells assessed as growth inhibition after 4 days by WST assay
|
Homo sapiens
|
26.6
nM
|
|
Journal : J. Med. Chem.
Title : A potent and highly efficacious Bcl-2/Bcl-xL inhibitor.
Year : 2013
Volume : 56
Issue : 7
First Page : 3048
Last Page : 3067
Authors : Aguilar A, Zhou H, Chen J, Liu L, Bai L, McEachern D, Yang CY, Meagher J, Stuckey J, Wang S.
Abstract : Our previously reported Bcl-2/Bcl-xL inhibitor, 4, effectively inhibited tumor growth but failed to achieve complete regression in vivo. We have now performed extensive modifications on its pyrrole core structure, which has culminated in the discovery of 32 (BM-1074). Compound 32 binds to Bcl-2 and Bcl-xL proteins with K(i) values of <1 nM and inhibits cancer cell growth with IC50 values of 1-2 nM in four small-cell lung cancer cell lines sensitive to potent and specific Bcl-2/Bcl-xL inhibitors. Compound 32 is capable of achieving rapid, complete, and durable tumor regression in vivo at a well-tolerated dose schedule. Compound 32 is the most potent and efficacious Bcl-2/Bcl-xL inhibitor reported to date.
|
SANGER: Inhibition of human NCI-H209 cell growth in a cell viability assay.
|
Homo sapiens
|
87.04
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H720 cell growth in a cell viability assay.
|
Homo sapiens
|
40.11
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NH-12 cell growth in a cell viability assay.
|
Homo sapiens
|
107.44
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NKM-1 cell growth in a cell viability assay.
|
Homo sapiens
|
16.99
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NMC-G1 cell growth in a cell viability assay.
|
Homo sapiens
|
811.21
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NTERA-S-cl-D1 cell growth in a cell viability assay.
|
Homo sapiens
|
500.19
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human OAW-28 cell growth in a cell viability assay.
|
Homo sapiens
|
783.7
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human OAW-42 cell growth in a cell viability assay.
|
Homo sapiens
|
961.46
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human P12-ICHIKAWA cell growth in a cell viability assay.
|
Homo sapiens
|
77.78
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human PA-1 cell growth in a cell viability assay.
|
Homo sapiens
|
956.42
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human QIMR-WIL cell growth in a cell viability assay.
|
Homo sapiens
|
42.87
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RD cell growth in a cell viability assay.
|
Homo sapiens
|
758.99
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RH-18 cell growth in a cell viability assay.
|
Homo sapiens
|
60.48
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RMG-I cell growth in a cell viability assay.
|
Homo sapiens
|
494.64
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RPMI-8226 cell growth in a cell viability assay.
|
Homo sapiens
|
456.52
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human RS4-11 cell growth in a cell viability assay.
|
Homo sapiens
|
25.87
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SK-NEP-1 cell growth in a cell viability assay.
|
Homo sapiens
|
72.13
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human SW1417 cell growth in a cell viability assay.
|
Homo sapiens
|
554.38
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human 697 cell growth in a cell viability assay.
|
Homo sapiens
|
108.39
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human A427 cell growth in a cell viability assay.
|
Homo sapiens
|
930.22
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human A704 cell growth in a cell viability assay.
|
Homo sapiens
|
426.7
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ALL-PO cell growth in a cell viability assay.
|
Homo sapiens
|
219.88
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ATN-1 cell growth in a cell viability assay.
|
Homo sapiens
|
47.33
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human BE-13 cell growth in a cell viability assay.
|
Homo sapiens
|
364.59
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human BEN cell growth in a cell viability assay.
|
Homo sapiens
|
239.68
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human BV-173 cell growth in a cell viability assay.
|
Homo sapiens
|
23.14
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human TGBC24TKB cell growth in a cell viability assay.
|
Homo sapiens
|
457.78
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human TGW cell growth in a cell viability assay.
|
Homo sapiens
|
46.33
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human WM-115 cell growth in a cell viability assay.
|
Homo sapiens
|
277.38
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CCRF-CEM cell growth in a cell viability assay.
|
Homo sapiens
|
335.29
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human CHP-134 cell growth in a cell viability assay.
|
Homo sapiens
|
163.06
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human COR-L88 cell growth in a cell viability assay.
|
Homo sapiens
|
365.4
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human D-283MED cell growth in a cell viability assay.
|
Homo sapiens
|
176.86
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human DB cell growth in a cell viability assay.
|
Homo sapiens
|
570.8
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human DOHH-2 cell growth in a cell viability assay.
|
Homo sapiens
|
410.23
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human DU-145 cell growth in a cell viability assay.
|
Homo sapiens
|
899.23
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human DU-4475 cell growth in a cell viability assay.
|
Homo sapiens
|
654.27
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ECC10 cell growth in a cell viability assay.
|
Homo sapiens
|
37.92
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EM-2 cell growth in a cell viability assay.
|
Homo sapiens
|
199.18
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EW-13 cell growth in a cell viability assay.
|
Homo sapiens
|
583.41
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EW-16 cell growth in a cell viability assay.
|
Homo sapiens
|
813.28
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EW-18 cell growth in a cell viability assay.
|
Homo sapiens
|
68.41
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EW-22 cell growth in a cell viability assay.
|
Homo sapiens
|
466.71
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EW-3 cell growth in a cell viability assay.
|
Homo sapiens
|
80.53
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human EoL-1-cell cell growth in a cell viability assay.
|
Homo sapiens
|
6.693
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HAL-01 cell growth in a cell viability assay.
|
Homo sapiens
|
725.49
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HCC1569 cell growth in a cell viability assay.
|
Homo sapiens
|
251.06
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HCC38 cell growth in a cell viability assay.
|
Homo sapiens
|
801.9
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HL-60 cell growth in a cell viability assay.
|
Homo sapiens
|
29.08
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HPAF-II cell growth in a cell viability assay.
|
Homo sapiens
|
926.28
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human HuO9 cell growth in a cell viability assay.
|
Homo sapiens
|
267.15
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human IST-SL1 cell growth in a cell viability assay.
|
Homo sapiens
|
353.43
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human J-RT3-T3-5 cell growth in a cell viability assay.
|
Homo sapiens
|
608.08
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KARPAS-45 cell growth in a cell viability assay.
|
Homo sapiens
|
78.15
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KE-37 cell growth in a cell viability assay.
|
Homo sapiens
|
113.7
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KG-1 cell growth in a cell viability assay.
|
Homo sapiens
|
44.86
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KNS-81-FD cell growth in a cell viability assay.
|
Homo sapiens
|
440.17
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KP-N-YN cell growth in a cell viability assay.
|
Homo sapiens
|
235.73
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human KY821 cell growth in a cell viability assay.
|
Homo sapiens
|
29.75
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LAMA-84 cell growth in a cell viability assay.
|
Homo sapiens
|
592.07
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LU-134-A cell growth in a cell viability assay.
|
Homo sapiens
|
186.71
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LU-135 cell growth in a cell viability assay.
|
Homo sapiens
|
185.52
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human LU-139 cell growth in a cell viability assay.
|
Homo sapiens
|
204.98
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MEG-01 cell growth in a cell viability assay.
|
Homo sapiens
|
583.2
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human ML-2 cell growth in a cell viability assay.
|
Homo sapiens
|
19.83
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MOLT-13 cell growth in a cell viability assay.
|
Homo sapiens
|
466.13
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MOLT-16 cell growth in a cell viability assay.
|
Homo sapiens
|
652.64
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MOLT-4 cell growth in a cell viability assay.
|
Homo sapiens
|
151.69
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MS-1 cell growth in a cell viability assay.
|
Homo sapiens
|
469.33
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human MV-4-11 cell growth in a cell viability assay.
|
Homo sapiens
|
15.86
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NB12 cell growth in a cell viability assay.
|
Homo sapiens
|
231.15
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NB13 cell growth in a cell viability assay.
|
Homo sapiens
|
82.03
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NB17 cell growth in a cell viability assay.
|
Homo sapiens
|
71.24
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H1048 cell growth in a cell viability assay.
|
Homo sapiens
|
509.53
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H1092 cell growth in a cell viability assay.
|
Homo sapiens
|
102.75
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
SANGER: Inhibition of human NCI-H1304 cell growth in a cell viability assay.
|
Homo sapiens
|
461.57
nM
|
|
Title : Genomics of Drug Sensitity in Cancer screening data, Wellcome Trust Sanger Institute
|
Displacement of FITC-Bid from GST-tagged human Bcl-xL expressed in Escherichia coli after 2 hrs by TR-FRET assay
|
Homo sapiens
|
3.3
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of potent Mcl-1/Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins.
Year : 2013
Volume : 56
Issue : 23
First Page : 9635
Last Page : 9645
Authors : Tanaka Y, Aikawa K, Nishida G, Homma M, Sogabe S, Igaki S, Hayano Y, Sameshima T, Miyahisa I, Kawamoto T, Tawada M, Imai Y, Inazuka M, Cho N, Imaeda Y, Ishikawa T.
Abstract : Mcl-1 and Bcl-xL are crucial regulators of apoptosis, therefore dual inhibitors of both proteins could serve as promising new anticancer drugs. To design Mcl-1/Bcl-xL dual inhibitors, we performed structure-guided analyses of the corresponding selective Mcl-1 and Bcl-xL inhibitors. A cocrystal structure of a pyrazolo[1,5-a]pyridine derivative with Mcl-1 protein was successfully determined and revealed the protein-ligand binding mode. The key structure for Bcl-xL inhibition was further confirmed through the substructural analysis of ABT-263, a representative Bcl-xL/Bcl-2/Bcl-w inhibitor developed by Abbott Laboratories. On the basis of the structural data from this analysis, we designed hybrid compounds by tethering the Mcl-1 and Bcl-xL inhibitors together. The results of X-ray crystallographic analysis of hybrid compound 10 in complexes with both Mcl-1 and Bcl-xL demonstrated its binding mode with each protein. Following further optimization, compound 11 showed potent Mcl-1/Bcl-xL dual inhibitory activity (Mcl-1, IC50 = 0.088 μM; and Bcl-xL, IC50 = 0.0037 μM).
|
Induction of apoptosis in human RS4:11 cells overexpressing BCL-2 assessed as caspase 3/7 activation after 6 hrs by quantitative luminescence assay
|
Homo sapiens
|
14.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Towards the next generation of dual Bcl-2/Bcl-xL inhibitors.
Year : 2014
Volume : 24
Issue : 14
First Page : 3026
Last Page : 3033
Authors : Varnes JG, Gero T, Huang S, Diebold RB, Ogoe C, Grover PT, Su M, Mukherjee P, Saeh JC, MacIntyre T, Repik G, Dillman K, Byth K, Russell DJ, Ioannidis S.
Abstract : Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.
|
Inhibition of human BCL-2 overexpressed in mouse FDC-P1 cells assessed as cell viability after 24 hrs by Cell Titer Glo assay
|
Homo sapiens
|
15.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Towards the next generation of dual Bcl-2/Bcl-xL inhibitors.
Year : 2014
Volume : 24
Issue : 14
First Page : 3026
Last Page : 3033
Authors : Varnes JG, Gero T, Huang S, Diebold RB, Ogoe C, Grover PT, Su M, Mukherjee P, Saeh JC, MacIntyre T, Repik G, Dillman K, Byth K, Russell DJ, Ioannidis S.
Abstract : Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.
|
Inhibition of human BCL-xL overexpressed in mouse FDC-P1 cells assessed as cell viability after 24 hrs by Cell Titer Glo assay
|
Homo sapiens
|
60.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Towards the next generation of dual Bcl-2/Bcl-xL inhibitors.
Year : 2014
Volume : 24
Issue : 14
First Page : 3026
Last Page : 3033
Authors : Varnes JG, Gero T, Huang S, Diebold RB, Ogoe C, Grover PT, Su M, Mukherjee P, Saeh JC, MacIntyre T, Repik G, Dillman K, Byth K, Russell DJ, Ioannidis S.
Abstract : Structural modifications of the left-hand side of compound 1 were identified which retained or improved potent binding to Bcl-2 and Bcl-xL in in vitro biochemical assays and had strong activity in an RS4;11 apoptotic cellular assay. For example, sulfoxide diastereomer 13 maintained good binding affinity and comparable cellular potency to 1 while improving aqueous solubility. The corresponding diastereomer (14) was significantly less potent in the cell, and docking studies suggest that this is due to a stereochemical preference for the RS versus SS sulfoxide. Appending a dimethylaminoethoxy side chain (27) adjacent to the benzylic position of the biphenyl moiety of 1 improved cellular activity by approximately three-fold, and this activity was corroborated in cell lines overexpressing Bcl-2 and Bcl-xL.
|
Inhibition of Bcl-xL/Bim (unknown origin) by ELISA
|
Homo sapiens
|
4.3
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and evaluation of marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors.
Year : 2015
Volume : 90
First Page : 315
Last Page : 331
Authors : Li R, Cheng C, Balasis ME, Liu Y, Garner TP, Daniel KG, Li J, Qin Y, Gavathiotis E, Sebti SM.
Abstract : Inhibition of anti-apoptotic Mcl-1 is a promising anticancer strategy to overcome the survival and chemoresistance of a broad spectrum of human cancers. We previously reported on the identification of a natural product marinopyrrole A (1) that induces apoptosis in Mcl-1-dependent cells through Mcl-1 degradation. Here, we report the design and synthesis of novel marinopyrrole-based analogs and their evaluation as selective inhibitors of Mcl-1 as well as dual Mcl-1/Bcl-xL inhibitors. The most selective Mcl-1 antagonists were 34, 36 and 37 with 16-, 13- and 9-fold more selectivity for disrupting Mcl-1/Bim over Bcl-xL/Bim binding, respectively. Among the most potent dual inhibitors is 42 which inhibited Mcl-1/Bim and Bcl-xL/Bim binding 15-fold (IC50 = 600 nM) and 33-fold (500 nM) more potently than (±)-marinopyrrole A (1), respectively. Fluorescence quenching, NMR analysis and molecular docking indicated binding of marinopyrroles to the BH3 binding site of Mcl-1. Several marinopyrroles potently decreased Mcl-1 cellular levels and induced caspase 3 activation in human breast cancer cells. Our studies provide novel "lead" marinopyrroles for further optimization as selective Mcl-1 inhibitors and dual Mcl-1 and Bcl-xL inhibitors.
|
Binding affinity to Bcl-2 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Selective inhibitors of Bcl-2 and Bcl-xL: Balancing antitumor activity with on-target toxicity.
Year : 2016
Volume : 26
Issue : 9
First Page : 2105
Last Page : 2114
Authors : Hennessy EJ.
Abstract : The induction of apoptosis in tumor cells represents a promising approach to the treatment of cancer. Accordingly, compounds that interact with the Bcl-2 family of proteins, which are critical regulators of the apoptotic process, have been widely pursued as potential anticancer agents. While encouraging antitumor activity in clinical trials has been observed with some of these compounds, their therapeutic utility is often limited by accompanying toxicities associated with the interaction with this family of proteins. As a result, there has been recent interest in identifying agents that can selectively target a single Bcl-2 family member (such as Bcl-2 or Bcl-xL), with the expectation that improved therapeutic margins can be achieved. In this review, we outline the biological rationale behind this approach, and highlight key examples of selective compounds from the recent literature alongside the structural basis for the reported selectivity.
|
Binding affinity to Bcl-XL (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Selective inhibitors of Bcl-2 and Bcl-xL: Balancing antitumor activity with on-target toxicity.
Year : 2016
Volume : 26
Issue : 9
First Page : 2105
Last Page : 2114
Authors : Hennessy EJ.
Abstract : The induction of apoptosis in tumor cells represents a promising approach to the treatment of cancer. Accordingly, compounds that interact with the Bcl-2 family of proteins, which are critical regulators of the apoptotic process, have been widely pursued as potential anticancer agents. While encouraging antitumor activity in clinical trials has been observed with some of these compounds, their therapeutic utility is often limited by accompanying toxicities associated with the interaction with this family of proteins. As a result, there has been recent interest in identifying agents that can selectively target a single Bcl-2 family member (such as Bcl-2 or Bcl-xL), with the expectation that improved therapeutic margins can be achieved. In this review, we outline the biological rationale behind this approach, and highlight key examples of selective compounds from the recent literature alongside the structural basis for the reported selectivity.
|
Binding affinity to BCL2 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : MedChemComm
Title : Small molecules targeting Mcl-1: the search for a silver bullet in cancer therapy
Year : 2016
Volume : 7
Issue : 5
First Page : 778
Last Page : 787
Authors : Nhu D, Lessene G, Huang DCS, Burns CJ
|
Binding affinity to MCL1 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
500.0
nM
|
|
Journal : MedChemComm
Title : Small molecules targeting Mcl-1: the search for a silver bullet in cancer therapy
Year : 2016
Volume : 7
Issue : 5
First Page : 778
Last Page : 787
Authors : Nhu D, Lessene G, Huang DCS, Burns CJ
|
Binding affinity to Bcl-XL (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
0.5
nM
|
|
Journal : MedChemComm
Title : Small molecules targeting Mcl-1: the search for a silver bullet in cancer therapy
Year : 2016
Volume : 7
Issue : 5
First Page : 778
Last Page : 787
Authors : Nhu D, Lessene G, Huang DCS, Burns CJ
|
Inhibition of Bcl-2 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : Eur J Med Chem
Title : Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents.
Year : 2018
Volume : 146
First Page : 471
Last Page : 482
Authors : Wan Y, Dai N, Tang Z, Fang H.
Abstract : The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. For example, the recently launched Bcl-2-selective inhibitor ABT-199 displays highly potency in the treatment of chronic lymphocytic leukemia (CLL), but it cannot induce the apoptosis controlled by Mcl-1 in some tumor cell lines. Therefore, developing potent Mcl-1 inhibitors become urgently needed in clinical therapy. This review briefly introduces the structure of Mcl-1 protein, the role in cancers and focuses on the progress of small-molecule Mcl-1 inhibitors from 2012 to 2017.
|
Inhibition of Bcl-xL (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : Eur J Med Chem
Title : Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents.
Year : 2018
Volume : 146
First Page : 471
Last Page : 482
Authors : Wan Y, Dai N, Tang Z, Fang H.
Abstract : The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. For example, the recently launched Bcl-2-selective inhibitor ABT-199 displays highly potency in the treatment of chronic lymphocytic leukemia (CLL), but it cannot induce the apoptosis controlled by Mcl-1 in some tumor cell lines. Therefore, developing potent Mcl-1 inhibitors become urgently needed in clinical therapy. This review briefly introduces the structure of Mcl-1 protein, the role in cancers and focuses on the progress of small-molecule Mcl-1 inhibitors from 2012 to 2017.
|
Inhibition of Mcl-1 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
550.0
nM
|
|
Journal : Eur J Med Chem
Title : Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents.
Year : 2018
Volume : 146
First Page : 471
Last Page : 482
Authors : Wan Y, Dai N, Tang Z, Fang H.
Abstract : The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members. For example, the recently launched Bcl-2-selective inhibitor ABT-199 displays highly potency in the treatment of chronic lymphocytic leukemia (CLL), but it cannot induce the apoptosis controlled by Mcl-1 in some tumor cell lines. Therefore, developing potent Mcl-1 inhibitors become urgently needed in clinical therapy. This review briefly introduces the structure of Mcl-1 protein, the role in cancers and focuses on the progress of small-molecule Mcl-1 inhibitors from 2012 to 2017.
|
Displacement of Bax-derived peptide from Bcl-2 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
10.3
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and pharmacological evaluation of new acyl sulfonamides as potent and selective Bcl-2 inhibitors.
Year : 2018
Volume : 26
Issue : 2
First Page : 443
Last Page : 454
Authors : Liu X, Zhang Y, Huang W, Tan W, Zhang A.
Abstract : The antiapoptotic protein Bcl-2, overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, we report a different structural modification approach on ABT-263 by merging the piperazinyl-phenyl fragment into a bicyclic framework leading to a series of novel analogues, among which tetrahydroisoquinoline 13 was nearly equally potent against Bcl-2 as ABT-263. Further SAR in the P4-interaction pocket affored the difluoroazetidine substituted analogue 55, which retained good Bcl-2 activity with improved Bcl-2/Bcl-xL selectivity.
|
Displacement of Bad-derived peptide from Bcl-XL (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
8.2
nM
|
|
Journal : Bioorg Med Chem
Title : Design, synthesis and pharmacological evaluation of new acyl sulfonamides as potent and selective Bcl-2 inhibitors.
Year : 2018
Volume : 26
Issue : 2
First Page : 443
Last Page : 454
Authors : Liu X, Zhang Y, Huang W, Tan W, Zhang A.
Abstract : The antiapoptotic protein Bcl-2, overexpressed in many tumor cells, is an attractive target for potential small molecule anticancer drug discovery. Herein, we report a different structural modification approach on ABT-263 by merging the piperazinyl-phenyl fragment into a bicyclic framework leading to a series of novel analogues, among which tetrahydroisoquinoline 13 was nearly equally potent against Bcl-2 as ABT-263. Further SAR in the P4-interaction pocket affored the difluoroazetidine substituted analogue 55, which retained good Bcl-2 activity with improved Bcl-2/Bcl-xL selectivity.
|
Inhibition of Bcl2 (unknown origin)
|
Homo sapiens
|
0.044
nM
|
|
Journal : J Med Chem
Title : Beyond the Rule of 5: Lessons Learned from AbbVie's Drugs and Compound Collection.
Year : 2018
Volume : 61
Issue : 7
First Page : 2636
Last Page : 2651
Authors : DeGoey DA, Chen HJ, Cox PB, Wendt MD.
Abstract : Recently, there has been an increasing focus on the pursuit of targets considered to be less druggable that offer potential for development of promising new therapeutic agents for the treatment of diseases with large unmet medical need, particularly in the areas of oncology and virology. However, conducting drug discovery campaigns in "beyond rule of 5" (bRo5) chemical space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective analysis of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compounds and improve the efficiency of drug design for future projects. We present here highlights and case studies of lessons learned from discovery of bRo5 compounds. A simple multiparametric scoring function (AB-MPS) was devised that correlated preclinical PK results with cLogD, number of rotatable bonds, and number of aromatic rings.
|
Inhibition of Bcl-xL (unknown origin)
|
Homo sapiens
|
0.055
nM
|
|
Journal : J Med Chem
Title : Beyond the Rule of 5: Lessons Learned from AbbVie's Drugs and Compound Collection.
Year : 2018
Volume : 61
Issue : 7
First Page : 2636
Last Page : 2651
Authors : DeGoey DA, Chen HJ, Cox PB, Wendt MD.
Abstract : Recently, there has been an increasing focus on the pursuit of targets considered to be less druggable that offer potential for development of promising new therapeutic agents for the treatment of diseases with large unmet medical need, particularly in the areas of oncology and virology. However, conducting drug discovery campaigns in "beyond rule of 5" (bRo5) chemical space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective analysis of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compounds and improve the efficiency of drug design for future projects. We present here highlights and case studies of lessons learned from discovery of bRo5 compounds. A simple multiparametric scoring function (AB-MPS) was devised that correlated preclinical PK results with cLogD, number of rotatable bonds, and number of aromatic rings.
|
Antiproliferative activity against human RS4:11 cells in presence of 10% human serum
|
Homo sapiens
|
112.0
nM
|
|
Journal : J Med Chem
Title : Beyond the Rule of 5: Lessons Learned from AbbVie's Drugs and Compound Collection.
Year : 2018
Volume : 61
Issue : 7
First Page : 2636
Last Page : 2651
Authors : DeGoey DA, Chen HJ, Cox PB, Wendt MD.
Abstract : Recently, there has been an increasing focus on the pursuit of targets considered to be less druggable that offer potential for development of promising new therapeutic agents for the treatment of diseases with large unmet medical need, particularly in the areas of oncology and virology. However, conducting drug discovery campaigns in "beyond rule of 5" (bRo5) chemical space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective analysis of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compounds and improve the efficiency of drug design for future projects. We present here highlights and case studies of lessons learned from discovery of bRo5 compounds. A simple multiparametric scoring function (AB-MPS) was devised that correlated preclinical PK results with cLogD, number of rotatable bonds, and number of aromatic rings.
|
Antiproliferative activity against human MOLT4 cells in presence of 10% human serum
|
Homo sapiens
|
303.0
nM
|
|
Journal : J Med Chem
Title : Beyond the Rule of 5: Lessons Learned from AbbVie's Drugs and Compound Collection.
Year : 2018
Volume : 61
Issue : 7
First Page : 2636
Last Page : 2651
Authors : DeGoey DA, Chen HJ, Cox PB, Wendt MD.
Abstract : Recently, there has been an increasing focus on the pursuit of targets considered to be less druggable that offer potential for development of promising new therapeutic agents for the treatment of diseases with large unmet medical need, particularly in the areas of oncology and virology. However, conducting drug discovery campaigns in "beyond rule of 5" (bRo5) chemical space presents a significant drug design and development challenge to medicinal chemists to achieve acceptable oral pharmacokinetics. Retrospective analysis of past successes and failures in drug discovery bRo5 may shed light on the key principles that contribute to the oral bioavailability of successful bRo5 compounds and improve the efficiency of drug design for future projects. We present here highlights and case studies of lessons learned from discovery of bRo5 compounds. A simple multiparametric scoring function (AB-MPS) was devised that correlated preclinical PK results with cLogD, number of rotatable bonds, and number of aromatic rings.
|
Inhibition of Bcl2 (unknown origin)
|
Homo sapiens
|
0.044
nM
|
|
Journal : J Med Chem
Title : Why Some Targets Benefit from beyond Rule of Five Drugs.
Year : 2019
Volume : 62
Issue : 22
First Page : 10005
Last Page : 10025
Authors : Egbert M, Whitty A, Keserű GM, Vajda S.
Abstract : Beyond rule-of-five (bRo5) compounds are increasingly used in drug discovery. Here we analyze 37 target proteins that have bRo5 drugs or clinical candidates. Targets can benefit from bRo5 drugs if they have "complex" hot spot structure with four or more hots spots, including some strong ones. Complex I targets show positive correlation between binding affinity and molecular weight. These targets are conventionally druggable, but reaching additional hot spots enables improved pharmaceutical properties. Complex II targets, mostly protein kinases, also have strong hot spots but show no correlation between affinity and ligand molecular weight, and the primary motivation for creating larger drugs is to increase selectivity. Each target considered as complex III has some specific reason for requiring bRo5 drugs. Finally, targets with "simple" hot spot structure, i.e., three or fewer weak hot spots, must use larger compounds that interact with surfaces beyond the hot spot region to achieve acceptable affinity.
|
Inhibition of BCL-XL (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
48.0
nM
|
|
Journal : Eur J Med Chem
Title : Clinical candidates modulating protein-protein interactions: The fragment-based experience.
Year : 2019
Volume : 167
First Page : 76
Last Page : 95
Authors : Valenti D, Hristeva S, Tzalis D, Ottmann C.
Abstract : Protein-protein interactions (PPIs) cover a very wide range of biological functions and consequently have become one of the favourite targets for new therapeutic strategies. PPIs are strongly characterised by an intricate and dynamic network of surface interactions occurring between two or more proteins. Because of the complexity of these interactions, many strategies have been applied with the aim to find selective modulators for a specific protein-protein complex. During the last decade, fragment-based approaches have served many drug discovery programs with an impressive increment of contributions, gaining a remarkable role in PPIs modulators' development. In this review, we detail the successful fragment-to-clinical candidate evolutions related to PPI modulation. An overview on the physico-chemical properties of both fragment hits and lead compounds will be presented together with a statistical analysis of their distribution.
|
Inhibition of BCL-2 (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
0.01
nM
|
|
Journal : Eur J Med Chem
Title : Clinical candidates modulating protein-protein interactions: The fragment-based experience.
Year : 2019
Volume : 167
First Page : 76
Last Page : 95
Authors : Valenti D, Hristeva S, Tzalis D, Ottmann C.
Abstract : Protein-protein interactions (PPIs) cover a very wide range of biological functions and consequently have become one of the favourite targets for new therapeutic strategies. PPIs are strongly characterised by an intricate and dynamic network of surface interactions occurring between two or more proteins. Because of the complexity of these interactions, many strategies have been applied with the aim to find selective modulators for a specific protein-protein complex. During the last decade, fragment-based approaches have served many drug discovery programs with an impressive increment of contributions, gaining a remarkable role in PPIs modulators' development. In this review, we detail the successful fragment-to-clinical candidate evolutions related to PPI modulation. An overview on the physico-chemical properties of both fragment hits and lead compounds will be presented together with a statistical analysis of their distribution.
|
Inhibition of BCL-W (unknown origin) by fluorescence polarization assay
|
Homo sapiens
|
245.0
nM
|
|
Journal : Eur J Med Chem
Title : Clinical candidates modulating protein-protein interactions: The fragment-based experience.
Year : 2019
Volume : 167
First Page : 76
Last Page : 95
Authors : Valenti D, Hristeva S, Tzalis D, Ottmann C.
Abstract : Protein-protein interactions (PPIs) cover a very wide range of biological functions and consequently have become one of the favourite targets for new therapeutic strategies. PPIs are strongly characterised by an intricate and dynamic network of surface interactions occurring between two or more proteins. Because of the complexity of these interactions, many strategies have been applied with the aim to find selective modulators for a specific protein-protein complex. During the last decade, fragment-based approaches have served many drug discovery programs with an impressive increment of contributions, gaining a remarkable role in PPIs modulators' development. In this review, we detail the successful fragment-to-clinical candidate evolutions related to PPI modulation. An overview on the physico-chemical properties of both fragment hits and lead compounds will be presented together with a statistical analysis of their distribution.
|
Toxicity in mouse xenografted with human haematological tumor at 12.5 mg/kg, po
|
Mus musculus
|
83.0
nM
|
|
Journal : Eur J Med Chem
Title : Clinical candidates modulating protein-protein interactions: The fragment-based experience.
Year : 2019
Volume : 167
First Page : 76
Last Page : 95
Authors : Valenti D, Hristeva S, Tzalis D, Ottmann C.
Abstract : Protein-protein interactions (PPIs) cover a very wide range of biological functions and consequently have become one of the favourite targets for new therapeutic strategies. PPIs are strongly characterised by an intricate and dynamic network of surface interactions occurring between two or more proteins. Because of the complexity of these interactions, many strategies have been applied with the aim to find selective modulators for a specific protein-protein complex. During the last decade, fragment-based approaches have served many drug discovery programs with an impressive increment of contributions, gaining a remarkable role in PPIs modulators' development. In this review, we detail the successful fragment-to-clinical candidate evolutions related to PPI modulation. An overview on the physico-chemical properties of both fragment hits and lead compounds will be presented together with a statistical analysis of their distribution.
|
Inhibition of Flu-Bax peptide binding to Bcl2 (unknown origin) by time-resolved fluorescence resonance energy transfer assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : Eur J Med Chem
Title : The chemical biology of apoptosis: Revisited after 17 years.
Year : 2019
Volume : 177
First Page : 63
Last Page : 75
Authors : Yang S, Mao Y, Zhang H, Xu Y, An J, Huang Z.
Abstract : A balance of Bcl-2 family proteins dictates cell survival or death, as the interactions between these proteins regulate mitochondrial apoptotic signaling pathways. However, cancer cells frequently show upregulation of pro-survival Bcl-2 proteins and sequester activated pro-apoptotic BH3-only proteins driven by diverse cytotoxic stresses, resulting in tumor progression and chemoresistance. Synthetic molecules from either structure-based design or screening procedures to engage and inactivate pro-survival Bcl-2 proteins and restore apoptotic process represent a chemical biological means of selectively killing malignant cells. 17 years ago, one of us reviewed on the discovery of novel Bcl-2 targeted agents [1]. Here we revisit this area and examine the progress and current status of small molecule Bcl-2 inhibitor development, demonstrating the Bcl-2 family as a valid target for cancer therapy and providing successful examples for the discovery of inhibitors that target protein-protein interactions.
|
Inhibition of Flu-Bax peptide binding to Bcl-xL (unknown origin) by time-resolved fluorescence resonance energy transfer assay
|
Homo sapiens
|
0.5
nM
|
|
Journal : Eur J Med Chem
Title : The chemical biology of apoptosis: Revisited after 17 years.
Year : 2019
Volume : 177
First Page : 63
Last Page : 75
Authors : Yang S, Mao Y, Zhang H, Xu Y, An J, Huang Z.
Abstract : A balance of Bcl-2 family proteins dictates cell survival or death, as the interactions between these proteins regulate mitochondrial apoptotic signaling pathways. However, cancer cells frequently show upregulation of pro-survival Bcl-2 proteins and sequester activated pro-apoptotic BH3-only proteins driven by diverse cytotoxic stresses, resulting in tumor progression and chemoresistance. Synthetic molecules from either structure-based design or screening procedures to engage and inactivate pro-survival Bcl-2 proteins and restore apoptotic process represent a chemical biological means of selectively killing malignant cells. 17 years ago, one of us reviewed on the discovery of novel Bcl-2 targeted agents [1]. Here we revisit this area and examine the progress and current status of small molecule Bcl-2 inhibitor development, demonstrating the Bcl-2 family as a valid target for cancer therapy and providing successful examples for the discovery of inhibitors that target protein-protein interactions.
|
Inhibition of Flu-Bax peptide binding to MCl-1 (unknown origin) by time-resolved fluorescence resonance energy transfer assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : Eur J Med Chem
Title : The chemical biology of apoptosis: Revisited after 17 years.
Year : 2019
Volume : 177
First Page : 63
Last Page : 75
Authors : Yang S, Mao Y, Zhang H, Xu Y, An J, Huang Z.
Abstract : A balance of Bcl-2 family proteins dictates cell survival or death, as the interactions between these proteins regulate mitochondrial apoptotic signaling pathways. However, cancer cells frequently show upregulation of pro-survival Bcl-2 proteins and sequester activated pro-apoptotic BH3-only proteins driven by diverse cytotoxic stresses, resulting in tumor progression and chemoresistance. Synthetic molecules from either structure-based design or screening procedures to engage and inactivate pro-survival Bcl-2 proteins and restore apoptotic process represent a chemical biological means of selectively killing malignant cells. 17 years ago, one of us reviewed on the discovery of novel Bcl-2 targeted agents [1]. Here we revisit this area and examine the progress and current status of small molecule Bcl-2 inhibitor development, demonstrating the Bcl-2 family as a valid target for cancer therapy and providing successful examples for the discovery of inhibitors that target protein-protein interactions.
|
Inhibition of recombinant human N-terminal GST-tagged Bcl-xl (1 to 209 residues) expressed in Escherichia coli using HyLite Fluor 647-labeled BIM peptide as substrate incubated for 120 to 180 mins by TR-FRET assay
|
Homo sapiens
|
8.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery and optimization of covalent Bcl-xL antagonists.
Year : 2019
Volume : 29
Issue : 23
First Page : 126682
Last Page : 126682
Authors : Mukherjee H, Su N, Belmonte MA, Hargreaves D, Patel J, Tentarelli S, Aquila B, Grimster NP.
Abstract : Over the last ten years, targeted covalent inhibition has become a key discipline within medicinal chemistry research, most notably in the development of oncology therapeutics. One area where this approach is underrepresented, however, is in targeting protein-protein interactions. This is primarily because these hydrophobic interfaces lack appropriately located cysteine residues to allow for standard conjugate addition chemistry. Herein, we report our development of the first covalent inhibitors of the antiapoptotic protein B-cell lymphoma extra-large (Bcl-xL), utilizing a sulfonyl fluoride (SF) warhead to selectively covalently modify tyrosine 101 of the BH3 domain-binding groove. These compounds display time-dependent inhibition in a biochemical assay and are cellularly active (U266B1). In addition, compound 7 was further elaborated to generate a chemical-biology probe molecule, which may find utility in understanding the intricacies of Bcl-xL biology.
|
Inhibition of recombinant human C-terminal 6xHis-tagged Bcl-2 (M1 to F212 residues) expressed in Escherichia coli using HyLite Fluor 647-labeled BIM peptide as substrate incubated for 120 to 180 mins by TR-FRET assay
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery and optimization of covalent Bcl-xL antagonists.
Year : 2019
Volume : 29
Issue : 23
First Page : 126682
Last Page : 126682
Authors : Mukherjee H, Su N, Belmonte MA, Hargreaves D, Patel J, Tentarelli S, Aquila B, Grimster NP.
Abstract : Over the last ten years, targeted covalent inhibition has become a key discipline within medicinal chemistry research, most notably in the development of oncology therapeutics. One area where this approach is underrepresented, however, is in targeting protein-protein interactions. This is primarily because these hydrophobic interfaces lack appropriately located cysteine residues to allow for standard conjugate addition chemistry. Herein, we report our development of the first covalent inhibitors of the antiapoptotic protein B-cell lymphoma extra-large (Bcl-xL), utilizing a sulfonyl fluoride (SF) warhead to selectively covalently modify tyrosine 101 of the BH3 domain-binding groove. These compounds display time-dependent inhibition in a biochemical assay and are cellularly active (U266B1). In addition, compound 7 was further elaborated to generate a chemical-biology probe molecule, which may find utility in understanding the intricacies of Bcl-xL biology.
|
Inhibition of recombinant human N-terminal 6xHis-tagged Bcl-w (M1 to R171) expressed in Escherichia coli using HyLite Fluor 647-labeled Bim peptide as substrate incubated for 120 to 180 mins by TR-FRET assay
|
Homo sapiens
|
70.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Discovery and optimization of covalent Bcl-xL antagonists.
Year : 2019
Volume : 29
Issue : 23
First Page : 126682
Last Page : 126682
Authors : Mukherjee H, Su N, Belmonte MA, Hargreaves D, Patel J, Tentarelli S, Aquila B, Grimster NP.
Abstract : Over the last ten years, targeted covalent inhibition has become a key discipline within medicinal chemistry research, most notably in the development of oncology therapeutics. One area where this approach is underrepresented, however, is in targeting protein-protein interactions. This is primarily because these hydrophobic interfaces lack appropriately located cysteine residues to allow for standard conjugate addition chemistry. Herein, we report our development of the first covalent inhibitors of the antiapoptotic protein B-cell lymphoma extra-large (Bcl-xL), utilizing a sulfonyl fluoride (SF) warhead to selectively covalently modify tyrosine 101 of the BH3 domain-binding groove. These compounds display time-dependent inhibition in a biochemical assay and are cellularly active (U266B1). In addition, compound 7 was further elaborated to generate a chemical-biology probe molecule, which may find utility in understanding the intricacies of Bcl-xL biology.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
16.33
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.1
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
|
Inhibition of BCL2 (unknown origin) by TR-FRET assay
|
Homo sapiens
|
0.5
nM
|
|
Journal : J Med Chem
Title : Fragment Linking Strategies for Structure-Based Drug Design.
Year : 2020
Volume : 63
Issue : 20.0
First Page : 11420
Last Page : 11435
Authors : Bancet A,Raingeval C,Lomberget T,Le Borgne M,Guichou JF,Krimm I
Abstract : Fragment-based drug discovery is a strategy widely used in both academia and pharmaceutical companies to generate small-molecule protein inhibitors and drug candidates. Among the approaches reported in the literature (growing, linking, and merging), the linking approach theoretically offers the opportunity to rapidly gain in binding energy. Nevertheless, this approach is poorly represented when considering the compounds currently in clinical trials. Here, we report an exhaustive view of the cases published so far in the literature, together with the methods used to identify the two initial fragments either simultaneously or successively. We review the different types of linkers published and discuss how these linkers are designed to obtain the lead compound. Mixing merging and linking methods, where the linker is duplicated from a known inhibitor, appears as an interesting strategy. To reach superadditivity, we propose to grow one of the fragments in order to minimize the distance between the two binders and then link the resulting compounds using flexible alkyl-derived linkers.
|
Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) at 20uM using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and 2 uM FAS incubated for 35 mins by MS analysis
|
Homo sapiens
|
90.1
%
|
|
Journal : Bioorg Med Chem
Title : Small-molecule active pharmaceutical ingredients of approved cancer therapeutics inhibit human aspartate/asparagine-β-hydroxylase.
Year : 2020
Volume : 28
Issue : 20.0
First Page : 115675
Last Page : 115675
Authors : Brewitz L,Tumber A,Zhang X,Schofield CJ
Abstract : Human aspartate/asparagine-β-hydroxylase (AspH) is a 2-oxoglutarate (2OG) dependent oxygenase that catalyses the hydroxylation of Asp/Asn-residues of epidermal growth factor-like domains (EGFDs). AspH is reported to be upregulated on the cell surface of invasive cancer cells in a manner distinguishing healthy from cancer cells. We report studies on the effect of small-molecule active pharmaceutical ingredients (APIs) of human cancer therapeutics on the catalytic activity of AspH using a high-throughput mass spectrometry (MS)-based inhibition assay. Human B-cell lymphoma-2 (Bcl-2)-protein inhibitors, including the (R)-enantiomer of the natural product gossypol, were observed to efficiently inhibit AspH, as does the antitumor antibiotic bleomycin A. The results may help in the design of AspH inhibitors with the potential of increased selectivity compared to the previously identified Fe(II)-chelating or 2OG-competitive inhibitors. With regard to the clinical use of bleomycin A and of the Bcl-2 inhibitor venetoclax, the results suggest that possible side-effects mediated through the inhibition of AspH and other 2OG oxygenases should be considered.
|
Inhibition of N-His6-tagged human AspH (315-755) expressed in Escherichia coli BL21 (DE3) using 1 uM hFX-CP as substrate mixture with 3 uM 2OG, 100 uM L-ascorbic acid and high 20 uM FAS incubated for 35 mins by MS analysis
|
Homo sapiens
|
800.0
nM
|
|
Journal : Bioorg Med Chem
Title : Small-molecule active pharmaceutical ingredients of approved cancer therapeutics inhibit human aspartate/asparagine-β-hydroxylase.
Year : 2020
Volume : 28
Issue : 20.0
First Page : 115675
Last Page : 115675
Authors : Brewitz L,Tumber A,Zhang X,Schofield CJ
Abstract : Human aspartate/asparagine-β-hydroxylase (AspH) is a 2-oxoglutarate (2OG) dependent oxygenase that catalyses the hydroxylation of Asp/Asn-residues of epidermal growth factor-like domains (EGFDs). AspH is reported to be upregulated on the cell surface of invasive cancer cells in a manner distinguishing healthy from cancer cells. We report studies on the effect of small-molecule active pharmaceutical ingredients (APIs) of human cancer therapeutics on the catalytic activity of AspH using a high-throughput mass spectrometry (MS)-based inhibition assay. Human B-cell lymphoma-2 (Bcl-2)-protein inhibitors, including the (R)-enantiomer of the natural product gossypol, were observed to efficiently inhibit AspH, as does the antitumor antibiotic bleomycin A. The results may help in the design of AspH inhibitors with the potential of increased selectivity compared to the previously identified Fe(II)-chelating or 2OG-competitive inhibitors. With regard to the clinical use of bleomycin A and of the Bcl-2 inhibitor venetoclax, the results suggest that possible side-effects mediated through the inhibition of AspH and other 2OG oxygenases should be considered.
|
Binding affinity to human full-length N-terminal His6-tagged Bcl2 (2 to 206 residues) expressed in Escherichia coli S12 extract by isothermal titration calorimetry
|
Homo sapiens
|
20.6
nM
|
|
Journal : J Med Chem
Title : Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2.
Year : 2020
Volume : 63
Issue : 22
First Page : 13733
Last Page : 13744
Authors : Wang Z,Song T,Guo Z,Cao K,Chen C,Feng Y,Wang H,Yin F,Zhou S,Dai J,Zhang Z
Abstract : Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction network between pT69/pS70 and R106/R109 residues prevents the phosphorylation sites from exposure to phosphatase and subsequent dephosphorylation. A Bcl-2-dephosphorylation probe, S1-6e, was designed by installing a carboxylic acid group to a Bcl-2 inhibitor. The carboxyl group competitively disrupts the interaction network between R106/R109 and pT69/pS70 and subsequently facilitates Bcl-2 dephosphorylation in living cells. As a result, S1-6e manifests a more effective apoptosis induction in pBcl-2-dependent cancer cells than other inhibitors exhibiting a similar binding affinity for Bcl-2. We believe that targeting the allosteric pathways interconnecting the core-functional domain and the phosphorylation site can be a general strategy for a rational design of site-specific dephosphorylating probes, since the allosteric pathway has been discovered in a variety of proteins.
|
Binding affinity to human full-length N-terminal His6-tagged Bcl2 R106A/R109A mutant expressed in Escherichia coli S12 extract by isothermal titration calorimetry
|
Homo sapiens
|
27.8
nM
|
|
Journal : J Med Chem
Title : Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2.
Year : 2020
Volume : 63
Issue : 22
First Page : 13733
Last Page : 13744
Authors : Wang Z,Song T,Guo Z,Cao K,Chen C,Feng Y,Wang H,Yin F,Zhou S,Dai J,Zhang Z
Abstract : Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction network between pT69/pS70 and R106/R109 residues prevents the phosphorylation sites from exposure to phosphatase and subsequent dephosphorylation. A Bcl-2-dephosphorylation probe, S1-6e, was designed by installing a carboxylic acid group to a Bcl-2 inhibitor. The carboxyl group competitively disrupts the interaction network between R106/R109 and pT69/pS70 and subsequently facilitates Bcl-2 dephosphorylation in living cells. As a result, S1-6e manifests a more effective apoptosis induction in pBcl-2-dependent cancer cells than other inhibitors exhibiting a similar binding affinity for Bcl-2. We believe that targeting the allosteric pathways interconnecting the core-functional domain and the phosphorylation site can be a general strategy for a rational design of site-specific dephosphorylating probes, since the allosteric pathway has been discovered in a variety of proteins.
|
Binding affinity to human full-length N-terminal His6-tagged prephosphorylated Bcl2 R106A/R109A mutant expressed in Escherichia coli S12 extract by isothermal titration calorimetry
|
Homo sapiens
|
30.6
nM
|
|
Journal : J Med Chem
Title : Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2.
Year : 2020
Volume : 63
Issue : 22
First Page : 13733
Last Page : 13744
Authors : Wang Z,Song T,Guo Z,Cao K,Chen C,Feng Y,Wang H,Yin F,Zhou S,Dai J,Zhang Z
Abstract : Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction network between pT69/pS70 and R106/R109 residues prevents the phosphorylation sites from exposure to phosphatase and subsequent dephosphorylation. A Bcl-2-dephosphorylation probe, S1-6e, was designed by installing a carboxylic acid group to a Bcl-2 inhibitor. The carboxyl group competitively disrupts the interaction network between R106/R109 and pT69/pS70 and subsequently facilitates Bcl-2 dephosphorylation in living cells. As a result, S1-6e manifests a more effective apoptosis induction in pBcl-2-dependent cancer cells than other inhibitors exhibiting a similar binding affinity for Bcl-2. We believe that targeting the allosteric pathways interconnecting the core-functional domain and the phosphorylation site can be a general strategy for a rational design of site-specific dephosphorylating probes, since the allosteric pathway has been discovered in a variety of proteins.
|
Inhibition of F-Bak binding to GST-tagged BCL-XL (unknown origin) measured after 1 hr by TR-FRET assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Based Design of A-1293102, a Potent and Selective BCL-X Inhibitor.
Year : 2021
Volume : 12
Issue : 6.0
First Page : 1011
Last Page : 1016
Authors : Tao ZF,Wang X,Chen J,Ingram JP,Jin S,Judge RA,Kovar PJ,Park C,Sun C,Wakefield BD,Zhou L,Zhang H,Elmore SW,Phillips DC,Judd AS,Leverson JD,Souers AJ
Abstract : BCL-X, an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-X inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-X inhibitor A-1155463 and the dual BCL-X/BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-X and both efficiently and selectively killed BCL-X-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-X, while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-X inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.
|
Inhibition of F-Bak binding to GST-tagged BCL2 (unknown origin) measured after 1 hr by TR-FRET assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Based Design of A-1293102, a Potent and Selective BCL-X Inhibitor.
Year : 2021
Volume : 12
Issue : 6.0
First Page : 1011
Last Page : 1016
Authors : Tao ZF,Wang X,Chen J,Ingram JP,Jin S,Judge RA,Kovar PJ,Park C,Sun C,Wakefield BD,Zhou L,Zhang H,Elmore SW,Phillips DC,Judd AS,Leverson JD,Souers AJ
Abstract : BCL-X, an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-X inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-X inhibitor A-1155463 and the dual BCL-X/BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-X and both efficiently and selectively killed BCL-X-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-X, while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-X inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.
|
Inhibition of F-Bak binding to GST-tagged MCL1 (unknown origin) measured after 1 hr by TR-FRET assay
|
Homo sapiens
|
224.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Based Design of A-1293102, a Potent and Selective BCL-X Inhibitor.
Year : 2021
Volume : 12
Issue : 6.0
First Page : 1011
Last Page : 1016
Authors : Tao ZF,Wang X,Chen J,Ingram JP,Jin S,Judge RA,Kovar PJ,Park C,Sun C,Wakefield BD,Zhou L,Zhang H,Elmore SW,Phillips DC,Judd AS,Leverson JD,Souers AJ
Abstract : BCL-X, an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-X inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-X inhibitor A-1155463 and the dual BCL-X/BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-X and both efficiently and selectively killed BCL-X-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-X, while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-X inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.
|
Cytotoxicity against human MOLT-4 cells assessed as reduction in cell viability measured after 48 hrs by celltiter-glo assay
|
Homo sapiens
|
300.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Based Design of A-1293102, a Potent and Selective BCL-X Inhibitor.
Year : 2021
Volume : 12
Issue : 6.0
First Page : 1011
Last Page : 1016
Authors : Tao ZF,Wang X,Chen J,Ingram JP,Jin S,Judge RA,Kovar PJ,Park C,Sun C,Wakefield BD,Zhou L,Zhang H,Elmore SW,Phillips DC,Judd AS,Leverson JD,Souers AJ
Abstract : BCL-X, an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-X inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-X inhibitor A-1155463 and the dual BCL-X/BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-X and both efficiently and selectively killed BCL-X-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-X, while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-X inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.
|
Cytotoxicity against human RS4-11 cells assessed as reduction in cell viability measured after 48 hrs by celltiter-glo assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : ACS Med Chem Lett
Title : Structure-Based Design of A-1293102, a Potent and Selective BCL-X Inhibitor.
Year : 2021
Volume : 12
Issue : 6.0
First Page : 1011
Last Page : 1016
Authors : Tao ZF,Wang X,Chen J,Ingram JP,Jin S,Judge RA,Kovar PJ,Park C,Sun C,Wakefield BD,Zhou L,Zhang H,Elmore SW,Phillips DC,Judd AS,Leverson JD,Souers AJ
Abstract : BCL-X, an antiapoptotic member of the BCL-2 family of proteins, drives tumor survival and maintenance and thus represents a key target for cancer treatment. Herein we report the rational design of a novel series of selective BCL-X inhibitors exemplified by A-1293102. This molecule contains structural elements of selective BCL-X inhibitor A-1155463 and the dual BCL-X/BCL-2 inhibitors ABT-737 and navitoclax, while representing a distinct pharmacophore as assessed by an objective cheminformatic evaluation. A-1293102 exhibited picomolar binding affinity to BCL-X and both efficiently and selectively killed BCL-X-dependent tumor cells. X-ray crystallographic analysis demonstrated a key hydrogen bonding network in the P2 binding pocket of BCL-X, while the bent-back moiety achieved efficient occupancy of the P4 pocket in a manner similar to that of navitoclax. A-1293102 represents one of the few distinct structural series of selective BCL-X inhibitors, and thus serves as a useful tool for biological studies as well as a lead compound for further optimization.
|
Antiproliferative activity against human MyLa1929 cells assessed as cell viability measured after 72 hrs by MTS assay
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of IAP-recruiting BCL-X PROTACs as potent degraders across multiple cancer cell lines.
Year : 2020
Volume : 199
First Page : 112397
Last Page : 112397
Authors : Zhang X,He Y,Zhang P,Budamagunta V,Lv D,Thummuri D,Yang Y,Pei J,Yuan Y,Zhou D,Zheng G
Abstract : Targeting BCL-X via PROTACs is a promising strategy in reducing BCL-X inhibition associated platelet toxicity. Recently, we reported potent BCL-X PROTAC degraders that recruit VHL or CRBN E3 ligase. However, low protein expression or mutation of the responsible E3 ligase has been known to result in decreased protein degradation efficiency of the corresponding PROTACs. To overcome these mechanisms of resistance, PROTACs based on recruiting alternative E3 ligases could be generated. Thus, we designed and synthesized a series of PROTACs that recruit IAP E3 ligases for BCL-X degradation. Among those PROTACs, compound 8a efficiently degrades BCL-X in malignant T-cell lymphoma cell line MyLa 1929 while CRBN-based PROTACs that have high potency in other cancer cell lines show compromised potency, likely due to the low CRBN expression. Moreover, compared with the parent compound ABT-263, PROTAC 8a shows comparable cell killing effects in MyLa 1929 cells whereas the on-target platelet toxicity is significantly reduced. Our findings expand the anti-tumor spectra of BCL-X degraders and further highlight the importance of selecting suitable E3 members to achieve effective cellular activity.
|
Cytotoxicity against human platelet assessed as cell viability measured after 72 hrs by MTS assay
|
Homo sapiens
|
189.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of IAP-recruiting BCL-X PROTACs as potent degraders across multiple cancer cell lines.
Year : 2020
Volume : 199
First Page : 112397
Last Page : 112397
Authors : Zhang X,He Y,Zhang P,Budamagunta V,Lv D,Thummuri D,Yang Y,Pei J,Yuan Y,Zhou D,Zheng G
Abstract : Targeting BCL-X via PROTACs is a promising strategy in reducing BCL-X inhibition associated platelet toxicity. Recently, we reported potent BCL-X PROTAC degraders that recruit VHL or CRBN E3 ligase. However, low protein expression or mutation of the responsible E3 ligase has been known to result in decreased protein degradation efficiency of the corresponding PROTACs. To overcome these mechanisms of resistance, PROTACs based on recruiting alternative E3 ligases could be generated. Thus, we designed and synthesized a series of PROTACs that recruit IAP E3 ligases for BCL-X degradation. Among those PROTACs, compound 8a efficiently degrades BCL-X in malignant T-cell lymphoma cell line MyLa 1929 while CRBN-based PROTACs that have high potency in other cancer cell lines show compromised potency, likely due to the low CRBN expression. Moreover, compared with the parent compound ABT-263, PROTAC 8a shows comparable cell killing effects in MyLa 1929 cells whereas the on-target platelet toxicity is significantly reduced. Our findings expand the anti-tumor spectra of BCL-X degraders and further highlight the importance of selecting suitable E3 members to achieve effective cellular activity.
|
Cytotoxicity against platelets in human PRP assessed as reduction in cell viability measured after 48 hrs by MTS assay
|
Homo sapiens
|
325.0
nM
|
|
|
Cytotoxicity against human RS4-11 cells assessed as reduction in cell viability measured after 48 hrs by MTS assay
|
Homo sapiens
|
42.6
nM
|
|
|
Cytotoxicity against human MOLT-4 cells assessed as reduction in cell viability measured after 48 hrs by MTS assay
|
Homo sapiens
|
212.3
nM
|
|
|
Displacement of biotin-tagged LWAAQRYGRELRRMSDEFEGSFKGL from human BCL-XL expressed in Escherichia coli measured after 2 hrs by AlphaScreen assay
|
Homo sapiens
|
2.07
nM
|
|
|
Displacement of biotin-tagged MRPEPATIAQELRRIGDEFNA from C-terminal His-tagged human BCL-2 (1` to 211 residues) expressed in Escherichia coli measured after 2 hrs by AlphaScreen assay
|
Homo sapiens
|
0.65
nM
|
|
