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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aniline Compounds / chemistry
-
Aniline Compounds / pharmacology
-
Aniline Compounds / therapeutic use
-
Animals
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology*
-
Antineoplastic Agents / 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
-
Myeloid Cell Leukemia Sequence 1 Protein / genetics
-
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
-
Proto-Oncogene Proteins / metabolism
-
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-bcl-2 / metabolism
-
RNA Interference
-
RNA, Small Interfering / metabolism
-
Sulfonamides / chemistry
-
Sulfonamides / pharmacology
-
Sulfonamides / therapeutic use
-
Transplantation, Heterologous
-
Tumor Suppressor Proteins / metabolism
-
bcl-2-Associated X Protein / metabolism
-
bcl-X Protein / antagonists & inhibitors*
-
bcl-X Protein / metabolism
Substances
-
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