Identification and Characterization of a Small Molecule Bcl-2 Functional Converter
dc.contributor.author | Kopparapu, Prasad R. | |
dc.contributor.author | Pearce, Martin C. | |
dc.contributor.author | Löhr, Christiane V. | |
dc.contributor.author | Duong, Cathy | |
dc.contributor.author | Jang, Hyo Sang | |
dc.contributor.author | Tyavanagimatt, Shanthakumar | |
dc.contributor.author | O’Donnell, Edmond F., III | |
dc.contributor.author | Nakshatri, Harikrishna | |
dc.contributor.author | Kolluri, Siva K. | |
dc.contributor.department | Surgery, School of Medicine | |
dc.date.accessioned | 2024-06-26T17:29:10Z | |
dc.date.available | 2024-06-26T17:29:10Z | |
dc.date.issued | 2024 | |
dc.description.abstract | 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. | |
dc.eprint.version | Final published version | |
dc.identifier.citation | Kopparapu 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-22-0526 | |
dc.identifier.uri | https://hdl.handle.net/1805/41931 | |
dc.language.iso | en_US | |
dc.publisher | American Association for Cancer Research | |
dc.relation.isversionof | 10.1158/2767-9764.CRC-22-0526 | |
dc.relation.journal | Cancer Research Communications | |
dc.rights | Attribution 4.0 International | en |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.source | PMC | |
dc.subject | Apoptosis regulatory proteins | |
dc.subject | Apoptosis | |
dc.subject | Protein binding | |
dc.title | Identification and Characterization of a Small Molecule Bcl-2 Functional Converter | |
dc.type | Article |