Identification and Characterization of a Small Molecule Bcl-2 Functional Converter

  • Cancer Res Commun. 2024 Mar 4;4(3):634-644. doi: 10.1158/2767-9764.CRC-22-0526.
Prasad R Kopparapu  1 ,  Martin C Pearce  1 ,  Christiane V Löhr  2 ,  Cathy Duong  1 ,  Hyo Sang Jang  1 ,  Shanthakumar Tyavanagimatt  1 ,  Edmond F O'Donnell 3rd  1 ,  Harikrishna Nakshatri  3 ,  Siva K Kolluri  1  4
Affiliations
  • 1. Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon.
  • 2. Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, Oregon.
  • 3. Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
  • 4. Linus Pauling Institute, Oregon State University, Corvallis, Oregon.
PMID: 38329389 DOI: 10.1158/2767-9764.CRC-22-0526
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.

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