A novel Hsp70 inhibitor specifically targeting the cancer-related Hsp70-Bim protein-protein interaction

• DOI: 10.1016/j.ejmech.2021.113452
• Publication Date: 2021-04-15T03:46:54Z
• Authors: Ziqian Wang; Ting Song; Zongwei Guo; Laura B. Uwituze; Yafei Guo; Hong Zhang; Hang Wang; Xiaodong Zhang; Hao Pan; Tong Ji; Fangkui Yin; Sheng Zhou; Jian Dai; Zhichao Zhang
• Keywords: Structure-Activity Relationship; 0303 health sciences; 03 medical and health sciences; Bcl-2-Like Protein 11; Dose-Response Relationship, Drug; Molecular Structure; Humans; Antineoplastic Agents; HSP70 Heat-Shock Proteins; Protein Binding; 3. Good health

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.