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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 Inhibition of breast cancer lung metastasis by BFC1108. A, BFC1108 suppresses the growth of lung metastasis in vivo. LMD-231 cells (200,000) stably expressing luciferase were injected into the tail vein of 6-week-old nude mice. Lung metastasis was detected in 2 weeks. Mice were randomized and were treated four times a week with vehicle or 100 mg/kg BFC1108 by intraperitoneal route (n = 8 for vehicle treatment and n = 9 for BFC1108 treatment). Bioluminescent imaging was performed once a week and quantified. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Bioluminescent imaging data for individual mouse treated with vehicle or BFC1108 are shown in Supplementary Fig. S2. B, Representative mouse image from vehicle and BFC treatment is shown. C, Treatment with BFC1108 does not alter body weight of mice. Body weights were measured each time the mice were imaged. D, Suppression of lung metastasis by BFC1108. H&E staining showed increased number of tumor cells in lung tissue of mice with vehicle treatment, compared with BFC1108 treatment, at the end of the study. E, BFC1108 reduces proliferation of lung metastatic TNBC cells. Detection of Ki-67 indicating proliferating tumor cells in lung tissue from vehicle and BFC1108-treated mice.
Funding
HHS | NIH | National Cancer Institute (NCI)
DOD | USA | MEDCOM | Congressionally Directed Medical Research Programs (CDMRP)
U.S. Department of Agriculture (USDA)
History
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.
