State Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, 116024, China.
State Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, 116024, China.
Eur J Med Chem. 2021 Aug 5;220:113452. doi: 10.1016/j.ejmech.2021.113452. Epub 2021 Apr 14.
Targeting cancer-related Hsp70-Bim protein-protein interactions (PPIs) offers a new strategy for the design of Hsp70 inhibitors. Herein, we discovered a novel Hsp70 inhibitor, S1g-6, based on the established BH3 mimetics. S1g-6 exhibited sub-μM binding affinity toward Hsp70 and selectively disrupted Hsp70-Bim PPI. The target specificity of S1g-6in situ was validated by affinity-based protein profiling, co-immunoprecipitation, and cell-based shRNA assays. S1g-6 specifically antagonized the ATPase activity of Hsp70 upon recruiting Bim and showed selective apoptosis induction in some cancer cell lines over normal ones through suppression of some oncogenic clients of Hsp70, representing a new class of antitumor candidates. Hsp70-Bim PPI exhibited cancer-dependent role as a potential anti-cancer target.
靶向与癌症相关的 HSP70-Bim 蛋白-蛋白相互作用（PPIs）为 HSP70 抑制剂的设计提供了新策略。本文基于已建立的 BH3 模拟物，发现了一种新型 HSP70 抑制剂 S1g-6。S1g-6 对 HSP70 具有亚微摩尔结合亲和力，并选择性地破坏 HSP70-Bim PPI。通过基于亲和力的蛋白质谱分析、共免疫沉淀和基于细胞的 shRNA 测定，验证了 S1g-6 在原位的靶标特异性。S1g-6 特异性地在募集 Bim 后拮抗 HSP70 的 ATP 酶活性，并通过抑制 HSP70 的一些致癌客户，选择性地在一些癌细胞系中诱导细胞凋亡，而在正常细胞中则没有，这代表了一类新的抗肿瘤候选物。Hsp70-Bim PPI 作为一种潜在的抗癌靶点，表现出了癌症依赖性的作用。
