Synthesis and Biological Evaluation of Apogossypolone Derivatives as Pan-active Inhibitors of Antiapoptotic B-Cell Lymphoma/Leukemia-2 (Bcl-2) Family Proteins
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- 作者：Jun Wei ; Shinichi Kitada ; John L. Stebbins ; William Placzek ; Dayong Zhai ; Bainan Wu ; Michele F. Rega ; Ziming Zhang ; Jason Cellitti ; Li Yang ; Russell Dahl ; John C. Reed ; Maurizio Pellecchia
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：November 25, 2010
- 年：2010
- 卷：53
- 期：22
- 页码：8000-8011
- 全文大小：1046K
- 年卷期：v.53,no.22(November 25, 2010)
- ISSN：1520-4804
文摘
Overexpression of antiapoptotic Bcl-2 family proteins is commonly related with tumor maintenance, progression, and chemoresistance. Inhibition of these antiapoptotic proteins is an attractive approach for cancer therapy. Guided by nuclear magnetic resonance (NMR) binding assays, a series of 5,5′ substituted compound 6a (Apogossypolone) derivatives was synthesized and identified pan-active antagonists of antiapoptotic Bcl-2 family proteins, with binding potency in the low micromolar to nanomolar range. Compound 6f inhibits the binding of BH3 peptides to Bcl-XL, Bcl-2, and Mcl-1 with IC50 values of 3.10, 3.12, and 2.05 μM, respectively. In a cellular assay, 6f potently inhibits cell growth in several human cancer cell lines in a dose-dependent manner. Compound 6f further displays in vivo efficacy in transgenic mice and demonstrated superior single-agent antitumor efficacy in a PPC-1 mouse xenograft model. Together with its negligible toxicity, compound 6f represents a promising drug lead for the development of novel apoptosis-based therapies for cancer.