Abstract 5: Synthesis and biological evaluation of 5, 5’ substituted apogossypol and apogossypolone derivatives as pan-active inhibitors of anti-apoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins

Abstract

Abstract Overexpression of anti-apoptotic Bcl-2 family proteins is commonly related with tumor maintenance, progression, and chemoresistance. Inhibition of these anti-apoptotic proteins is an attractive approach for cancer therapy. Guided by nuclear magnetic resonance (NMR) binding assays and computational docking studies, a series of 5, 5’ substituted Apogossypol and Apogossypolone derivatives was synthesized and identified pan-active antagonists of anti-apoptotic Bcl-2 family proteins, with binding potency in the low micromolar to nanomolar range. Apogossypol derivative BI97C1 inhibits the binding of BH3 peptides to Bcl-XL, Bcl-2 and Mcl-1 with IC50 values of 0.31, 0.32 and 0.20 µM, respectively. In a cellular assay, BI97C1 potently inhibits cell growth in the H460 human lung cancer and PC-3 human prostate cancer cell lines with EC50 values of 0.40 and 0.13 µM, respectively, and effectively induces apoptosis of the BP3 human lymphoma cell line (EC50 = 0.049 µM) in a dose-dependent manner. Apogossypolone derivative BI97D1 also potently inhibit cell growth in many cancer cell lines. BI97C1 and BI97D1 further display in vivo efficacy in transgenic mice in which Bcl-2 is overexpressed in splenic B-cells and also demonstrated superior single-agent antitumor efficacy in mouse xenograft model and represent promising drug leads for the development of novel apoptosis-based therapies for cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5. doi:10.1158/1538-7445.AM2011-5