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

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

doi:10.1016/j.ejmech.2021.113452

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

Eur J Med Chem. 2021 Aug 5:220:113452. doi: 10.1016/j.ejmech.2021.113452. Epub 2021 Apr 14.

Authors

Ziqian Wang¹, Ting Song², Zongwei Guo³, Laura B Uwituze¹, Yafei Guo³, Hong Zhang³, Hang Wang³, Xiaodong Zhang¹, Hao Pan¹, Tong Ji¹, Fangkui Yin¹, Sheng Zhou¹, Jian Dai¹, Zhichao Zhang⁴

Affiliations

¹ State Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, 116024, China.
² State Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, 116024, China. Electronic address: songting@dlut.edu.cn.
³ School of Bioengineering, Dalian University of Technology, Dalian, Liaoning, 116024, China.
⁴ State Key Laboratory of Fine Chemicals, Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, Liaoning, 116024, China. Electronic address: zczhang@dlut.edu.cn.

PMID: 33906046
DOI: 10.1016/j.ejmech.2021.113452

Abstract

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.

Keywords: Antitumor candidate; Cancer-related target; Hsp70 inhibitor; Hsp70-bim PPI.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Bcl-2-Like Protein 11 / antagonists & inhibitors*
Bcl-2-Like Protein 11 / chemistry
Dose-Response Relationship, Drug
HSP70 Heat-Shock Proteins / antagonists & inhibitors*
HSP70 Heat-Shock Proteins / chemistry
Humans
Molecular Structure
Protein Binding
Structure-Activity Relationship

Substances

Antineoplastic Agents
Bcl-2-Like Protein 11
HSP70 Heat-Shock Proteins