Kopparapu, Prasad R.Pearce, Martin C.Löhr, Christiane V.Duong, CathyJang, Hyo SangTyavanagimatt, ShanthakumarO’Donnell, Edmond F., IIINakshatri, HarikrishnaKolluri, Siva K.2024-06-262024-06-262024Kopparapu PR, Pearce MC, Löhr CV, et al. Identification and Characterization of a Small Molecule Bcl-2 Functional Converter. Cancer Res Commun. 2024;4(3):634-644. doi:10.1158/2767-9764.CRC-22-0526https://hdl.handle.net/1805/41931Cancer 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.en-USAttribution 4.0 InternationalApoptosis regulatory proteinsApoptosisProtein bindingArticle