BI-97C1, an Optically Pure Apogossypol Derivative as Pan-Active Inhibitor of Antiapoptotic B-Cell Lymphoma/Leukemia-2 (Bcl-2) Family Proteins

Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 05/2010; 53(10):4166-76. DOI: 10.1021/jm1001265
Source: PubMed


In our continued attempts to identify novel and effective pan-Bcl-2 antagonists, we have recently reported a series of compound 2 (Apogossypol) derivatives, resulting in the chiral compound 4 (8r). We report here the synthesis and evaluation on its optically pure individual isomers. Compound 11 (BI-97C1), the most potent diastereoisomer of compound 4, inhibits the binding of BH3 peptides to Bcl-X(L), Bcl-2, Mcl-1, and Bfl-1 with IC(50) values of 0.31, 0.32, 0.20, and 0.62 microM, respectively. The compound also potently inhibits cell growth of human prostate cancer, lung cancer, and lymphoma cell lines with EC(50) values of 0.13, 0.56, and 0.049 microM, respectively, and shows little cytotoxicity against bax(-/-)bak(-/-) cells. Compound 11 displays in vivo efficacy in transgenic mice models and also demonstrated superior single-agent antitumor efficacy in a prostate cancer mouse xenograft model. Therefore, compound 11 represents a potential drug lead for the development of novel apoptosis-based therapies against cancer.

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Available from: William Placzek, Feb 10, 2014
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    • "anti-tumor chemotherapeutic agents over the life span of the patient may be necessary to provide enduring clinical responses (Di Lorenzo and De Placido, 2006; Damber and Aus, 2008). Previous studies demonstrated that BI-97C1 (Sabutoclax), which is a pure optical derivative of Apogossypol (Wei et al., 2010), has significant activity as a single agent against PC cells in vitro and in vivo in nude mouse xenograft studies. Apogossypol derivatives antagonize the anti-apoptotic Bcl-2 family members including Bcl-2 and myeloid cell leukemia-1 (Mcl-1) (Wei et al., 2009). "
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