Discovery of a Small‐Molecule pBcl‐2 Inhibitor that Overcomes pBcl‐2‐Mediated Resistance to Apoptosis. Issue 5 (25th February 2015)

• Record Type: Journal Article
• Authors: Song, Ting; Yu, Xiaoyan; Liu, Yubo; Li, Xiangqian; Chai, Gaobo; Zhang, Zhichao
• Is Part Of: Chembiochem. Volume 16:Issue 5(2015)
• Page Start: 757
• Page End: 765
• Publication Date: 2015-02-25
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201402639
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Although the role of Bcl‐2 phosphorylation is still under debate, it has been identified in a resistance mechanism to BH3 mimetics, for example ABT‐737 and <bold>S1</bold>. We identified an <bold>S1</bold> analogue, <bold>S1‐16</bold>, as a small‐molecule inhibitor of pBcl‐2. <bold>S1‐16</bold> efficiently kills EEE‐Bcl‐2 (a T69E, S70E, and S87E mutant mimicking phosphorylation)‐expressing HL‐60 cells and high endogenously expressing pBcl‐2 cells, by disrupting EEE‐Bcl‐2 or native pBcl‐2 interactions with Bax and Bak, followed by apoptosis. In vitro binding assays showed that <bold>S1‐16</bold> binds to the BH3 binding groove of EEE‐Bcl‐2 (<italic>K</italic>_d=0.38 μ<sc>M</sc> by ITC; IC₅₀=0.16 μ<sc>M</sc> by ELISA), as well as nonphosphorylated Bcl‐2 (npBcl‐2; <italic>K</italic>_d=0.38 μ<sc>M</sc>; IC₅₀=0.12 μ<sc>M</sc>). However, ABT‐737 and <bold>S1</bold> had much weaker affinities to EEE‐Bcl‐2 (IC₅₀=1.43 and &gt;10 μ<sc>M</sc>, respectively), compared with npBcl‐2 (IC₅₀=0.011 and 0.74 μ<sc>M</sc>, respectively). The allosteric effect on BH3 binding groove by Bcl‐2 phosphorylation in the loop region was illustrated for the first time.</p> </abstract>