Identification and Characterization of a Small Molecule Bcl-2 Functional Converter.

Autor:	Kopparapu PR; Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon., Pearce MC; Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon., Löhr CV; Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, Oregon., Duong C; Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon., Jang HS; Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon., Tyavanagimatt S; Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon., O'Donnell EF 3rd; Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon., Nakshatri H; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana., Kolluri SK; Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon.; Linus Pauling Institute, Oregon State University, Corvallis, Oregon.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Mar 04; Vol. 4 (3), pp. 634-644.
DOI:	10.1158/2767-9764.CRC-22-0526
Abstrakt:	Cancer cells exploit the expression of anti-apoptotic protein Bcl-2 to evade apoptosis and develop resistance to therapeutics. High levels of Bcl-2 leads to sequestration of pro-apoptotic proteins causing the apoptotic machinery to halt. In this study, we report discovery of a small molecule, BFC1108 (5-chloro-N-(2-ethoxyphenyl)-2-[(4-methoxybenzyol)amino]benzamide), which targets Bcl-2 and converts it into a pro-apoptotic protein. The apoptotic effect of BFC1108 is not inhibited, but rather potentiated, by Bcl-2 overexpression. BFC1108 induces a conformational change in Bcl-2, resulting in the exposure of its BH3 domain both in vitro and in vivo. BFC1108 suppresses the growth of triple-negative breast cancer xenografts with high Bcl-2 expression and inhibits breast cancer lung metastasis. This study demonstrates a novel approach to targeting Bcl-2 using BFC1108, a small molecule Bcl-2 functional converter that effectively induces apoptosis in Bcl-2-expressing cancers. Significance: We report the identification of a small molecule that exposes the Bcl-2 killer conformation and induces death in Bcl-2-expressing cancer cells. Selective targeting of Bcl-2 and elimination of cancer cells expressing Bcl-2 opens up new therapeutic avenues. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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