title: BM-1197: a novel and specific Bcl-2/Bcl-xL inhibitor inducing complete and long-lasting tumor regression in vivo.
abstract: Bcl-2 and Bcl-xL are critical regulators of apoptosis that are overexpressed in a variety of human cancers and pharmacological inhibition of Bcl-2 and Bcl-xL represents a promising strategy for cancer treatment. Using a structure-based design approach, we have designed BM-1197 as a potent and efficacious dual inhibitor of Bcl-2 and Bcl-xL. BM-1197 binds to Bcl-2 and Bcl-xL proteins with Ki values less than 1 nM and shows >1,000-fold selectivity over Mcl-1. Mechanistic studies performed in the Mcl-1 knockout mouse embryonic fibroblast (MEF) cells revealed that BM-1197 potently disassociates the heterodimeric interactions between anti-apoptotic and pro-apoptotic Bcl-2 family proteins, concomitant with conformational changes in Bax protein, loss of mitochondrial membrane potential and subsequent cytochrome c release to the cytosol, leading to activation of the caspase cascade and apoptosis. BM-1197 exerts potent growth-inhibitory activity in 7 of 12 small cell lung cancer cell lines tested and induces mechanism-based apoptotic cell death. When intravenously administered at daily or weekly in H146 and H1963 small-cell lung cancer xenograft models, it achieves complete and long-term tumor regression. Consistent with its targeting of Bcl-xL, BM-1197 causes transit platelet reduction in mice. Collectively, our data indicate that BM-1197 is a promising dual Bcl-2/Bcl-xL inhibitor which warrants further investigation as a new anticancer drug.
authors.affiliation: University of Michigan Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Longchuan
authors.initials: L
authors.lastname: Bai
authors.affiliation: University of Michigan Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Chen
authors.affiliation: University of Michigan Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Donna
authors.initials: D
authors.lastname: McEachern
authors.affiliation: University of Michigan Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.affiliation: University of Michigan Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Haibin
authors.initials: H
authors.lastname: Zhou
authors.affiliation: University of Michigan Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Angelo
authors.initials: A
authors.lastname: Aguilar
authors.affiliation: University of Michigan Comprehensive Cancer Center and Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America; University of Michigan Comprehensive Cancer Center and Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, United States of America; University of Michigan Comprehensive Cancer Center and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C000600257:BM-1197; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C579095:MCL1 protein, human; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013449:Sulfonamides; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D045304:Cytochromes c; C528561:navitoclax