Title | Identification and Characterization of a Small Molecule Bcl-2 Functional Converter. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Kopparapu PR, Pearce MC, Löhr CV, Duong C, Jang HSang, Tyavanagimatt S, O'Donnell EF, Nakshatri H, Kolluri SK |
Journal | Cancer Res Commun |
Volume | 4 |
Issue | 3 |
Pagination | 634-644 |
Date Published | 2024 Mar 04 |
ISSN | 2767-9764 |
Keywords | Apoptosis, Apoptosis Regulatory Proteins, Humans, Protein Binding |
Abstract | 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. |
DOI | 10.1158/2767-9764.CRC-22-0526 |
Alternate Journal | Cancer Res Commun |
PubMed ID | 38329389 |
PubMed Central ID | PMC10911799 |
Grant List | R21 CA249627 / CA / NCI NIH HHS / United States |