Abstract：
Clinical and biological studies have shown that overexpression of BFL-1 is one contributing factor to venetoclax resistance. The resistance might be overcome by a potent BFL-1 inhibitor, but such an inhibitor is rare. In this study, we show that 56, featuring an acrylamide moiety, inhibited the BFL-1/BID interaction with a Ki value of 105 nM. More interestingly, 56 formed an irreversible conjugation adduct at the C55 residue of BFL-1. 56 was a selective BFL-1 inhibitor, and its MCL-1 binding affinity was 10-fold weaker, while it did not bind BCL-2 and BCL-xL. Mechanistic studies showed that 56 overcame venetoclax resistance in isogenic AML cell lines MOLM-13-OE and MV4-11-OE, which both overexpressed BFL-1. More importantly, 56 and venetoclax combination promoted stronger apoptosis induction than either single agent. Collectively, our data show that 56 overcame resistance to venetoclax in AML cells overexpressing BFL-1. These attributes make 56 a promising candidate for future optimization.
摘要：
临床和生物学研究表明，BFL-1的过表达是维奈托克耐药的一个促成因素。这种抗性可以通过有效的BFL-1抑制剂来克服，但是这种抑制剂很少见。在这项研究中,我们显示56，具有丙烯酰胺部分，抑制BFL-1/BID相互作用，Ki值为105nM。更有趣的是，56在BFL-1的C55残基处形成不可逆的共轭加合物。56是选择性BFL-1抑制剂，它的MCL-1结合亲和力弱10倍，而它不结合BCL-2和BCL-xL。机制研究表明，在等基因AML细胞系MOLM-13-OE和MV4-11-OE中，有56种克服了venetoclax抗性，两者都过表达BFL-1。更重要的是,56和维奈托克的组合比任何一种单一药物都能促进更强的凋亡诱导。总的来说，我们的数据显示,在过表达BFL-1的AML细胞中,56例克服了对venetoclax的耐药性.这些属性使56成为未来优化的有希望的候选者。
