TitleIdentification and Characterization of a Small Molecule Bcl-2 Functional Converter.
Publication TypeJournal Article
Year of Publication2024
AuthorsKopparapu PR, Pearce MC, Löhr CV, Duong C, Jang HSang, Tyavanagimatt S, O'Donnell EF, Nakshatri H, Kolluri SK
JournalCancer Res Commun
Date Published2024 Mar 04
KeywordsApoptosis, Apoptosis Regulatory Proteins, Humans, Protein Binding

UNLABELLED: 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.

Alternate JournalCancer Res Commun
PubMed ID38329389
PubMed Central IDPMC10911799
Grant ListR21 CA249627 / CA / NCI NIH HHS / United States