The anti-apoptotic protein inhibitors of the B cell lymphoma 2 (Bcl-2) family have been developed as new anticancer therapies. Numerous studies illustrated the great potential in the development of dual Bcl-2/myeloid cell leukemia 1 (Mcl-1) inhibitors. Herein, we reported a series of Bcl-2/Mcl-1 inhibitors that optimized from a hit compound 1 via structure-based rational design. The biological evaluation suggested that most compounds exhibited potent binding affinities at submicromolar to both Bcl-2 and Mcl-1 without any Bcl-xL binding affinities, especially compound 9o, with a K_i value of 0.07 μM to Mcl-1 and 0.66 μM to Bcl-2, that has great potential for developing dual inhibitors targeting Bcl-2 and Mcl-1.

B 细胞淋巴瘤 2 (Bcl-2) 家族的抗凋亡蛋白抑制剂已被开发为新的抗癌疗法。大量研究表明，开发双重 Bcl-2/骨髓细胞白血病 1 (Mcl-1) 抑制剂具有巨大潜力。在此，我们报道了一系列 Bcl-2/Mcl-1 抑制剂，它们通过基于结构的合理设计从命中化合物 1 中优化。生物学评估表明，大多数化合物对 Bcl-2 和 Mcl-1 均表现出亚微摩尔的强结合亲和力，而没有任何 Bcl-xL 结合亲和力，尤其是化合物 9o，对 Mcl-1的K _i值为 0.07 μM，对 Mcl-1的K _i值为 0.66 μM。 Bcl-2，具有开发针对 Bcl-2 和 Mcl-1 的双重抑制剂的巨大潜力。