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	Longchuan Bai, Jianfang Chen, Donna McEachern, Liu Liu, Haibin Zhou, Angelo Aguilar, Shaomeng Wang
Journal	PloS one (PLoS One) Vol. 9 Issue 6 Pg. e99404 ( 2014) ISSN: 1932-6203 [Electronic] United States
PMID	24901320 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Aniline Compounds Antineoplastic Agents Apoptosis Regulatory Proteins BCL2L11 protein, human BM-1197 Bcl-2-Like Protein 11 Bcl2l11 protein, mouse MCL1 protein, human Membrane Proteins Myeloid Cell Leukemia Sequence 1 Protein PUMA protein, mouse Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 RNA, Small Interfering Sulfonamides Tumor Suppressor Proteins bcl-2-Associated X Protein bcl-X Protein Cytochromes c navitoclax
Topics	Aniline Compounds (chemistry, pharmacology, therapeutic use) Animals Antineoplastic Agents (chemistry, pharmacology, therapeutic use) Apoptosis (drug effects) Apoptosis Regulatory Proteins (metabolism) Bcl-2-Like Protein 11 Cell Line Cytochromes c (metabolism) Humans Lung Neoplasms (drug therapy) Membrane Proteins (metabolism) Mice Mice, SCID Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors, genetics, metabolism) Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors, metabolism) RNA Interference RNA, Small Interfering (metabolism) Sulfonamides (chemistry, pharmacology, therapeutic use) Transplantation, Heterologous Tumor Suppressor Proteins (metabolism) bcl-2-Associated X Protein (metabolism) bcl-X Protein (antagonists & inhibitors, metabolism)

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