American Association for Cancer Research
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Supplemental Figure 1 from Identification and Characterization of a Small Molecule Bcl-2 Functional Converter

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journal contribution
posted on 2024-03-04, 22:24 authored by Prasad R. Kopparapu, Martin C. Pearce, Christiane V. Löhr, Cathy Duong, Hyo Sang Jang, Shanthakumar Tyavanagimatt, Edmond F. O'Donnell, Harikrishna Nakshatri, Siva K. Kolluri

Bcl-2 dependent apoptotic effects of BFC1108. Independent experimental replicates of data in Figure 2C are shown.

Funding

HHS | NIH | National Cancer Institute (NCI)

DOD | USA | MEDCOM | Congressionally Directed Medical Research Programs (CDMRP)

U.S. Department of Agriculture (USDA)

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ARTICLE 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. 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.