Anti-apoptotic Bcl-2 family proteins are overexpressed in a wide spectrum of cancers and have become well validated therapeutic targets. Cancer cells display survival dependence on individual or subsets of anti-apoptotic proteins that could be effectively targeted by multimodal inhibitors. We designed a 2,5-substituted benzoic acid scaffold that displayed equipotent binding to Mcl-1 and Bfl-1. Structure-based design was guided by several solved cocrystal structures with Mcl-1, leading to the development of compound 24, which binds both Mcl-1 and Bfl-1 with Ki values of 100 nM and shows appreciable selectivity over Bcl-2/Bcl-xL. The selective binding profile of 24 was translated to on-target cellular activity in model lymphoma cell lines. These studies lay a foundation for developing more advanced dual Mcl-1/Bfl-1 inhibitors that have potential to provide greater single agent efficacy and broader coverage to combat resistance in several types of cancer than selective Mcl-1 inhibitors alone.

中文翻译：

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发现和表征抗凋亡Mcl-1和Bfl-1蛋白的2,5-取代的苯甲酸双重抑制剂。

抗凋亡的Bcl-2家族蛋白在多种癌症中均过表达，并已成为公认的治疗靶标。癌细胞显示出对单个或部分抗凋亡蛋白的生存依赖性，而抗凋亡蛋白可以被多峰抑制剂有效靶向。我们设计了2,5-取代的苯甲酸支架，该支架表现出与Mcl-1和Bfl-1的等价结合。基于结构的设计受Mcl-1的几种共晶结构的指导，从而导致化合物24的开发，该化合物结合Mcl-1和Bfl-1的Ki值为100 nM，并显示出超过Bcl-2 / Bcl的选择性-xL。在模型淋巴瘤细胞系中，将24的选择性结合谱转化为靶细胞活性。