Selective Mcl-1 inhibitors may overcome the drug resistance caused by current anti-apoptotic Bcl-2 protein inhibitors in tumors with Mcl-1 overexpression. Based on previously discovered compounds with a 3-phenylthiophene-2-sulfonamide core moiety, in this work, we have obtained new compounds with improved binding affinity and/or selectivity under the guidance of structure-based design. The most potent compounds achieved sub-micromolar binding affinities to Mcl-1 (K_i ∼ 0.4 μM) and good cytotoxicity (IC₅₀ < 10 μM) on several tumor cells. ¹⁵N-heteronuclear single-quantum coherence NMR spectra suggested that these compounds bound to the BH3-binding groove on Mcl-1. Several cellular assays revealed that FWJ-D4 as well as its precursor FWJ-D5 effectively induced caspase-dependent apoptosis, and their target engagement at Mcl-1 was confirmed by co-immunoprecipitation experiments. Treatment with FWJ-D5 at 50 mg/kg every 2 days on an RS4;11 xenograft mouse model for 22 days led to 75% reduction in tumor volume without body weight loss.

中文翻译：

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3-苯基-N-(2-(3-苯基脲基)乙基)噻吩-2-磺酰胺衍生物作为选择性Mcl-1抑制剂的基于结构的优化

选择性 Mcl-1 抑制剂可能克服当前抗凋亡 Bcl-2 蛋白抑制剂在 Mcl-1 过表达肿瘤中引起的耐药性。基于先前发现的具有 3-苯基噻吩-2-磺酰胺核心部分的化合物，在这项工作中，我们在基于结构的设计指导下获得了具有更高结合亲和力和/或选择性的新化合物。最有效的化合物对 Mcl-1 实现了亚微摩尔的结合亲和力 ( K _i ∼ 0.4 μM) 和对几种肿瘤细胞的良好细胞毒性 (IC ₅₀ < 10 μM)。¹⁵ N-异核单量子相干核磁共振谱表明这些化合物与 Mcl-1 上的 BH3 结合沟结合。多项细胞分析表明FWJ-D4以及其前体FWJ-D5有效诱导 caspase 依赖性细胞凋亡，并且它们在 Mcl-1 上的靶标参与通过共免疫沉淀实验得到证实。在 RS4;11 异种移植小鼠模型上，每 2 天用 50 毫克/千克的FWJ-D5治疗22 天，导致肿瘤体积减少 75%，而没有体重减轻。