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

Wang Ziqian; Song Ting; Guo Zongwei; Uwituze Laura B.; Guo Yafei; Zhang Hong; Wang Hang; Zhang Xiaodong; Pan Hao; Ji Tong; Yin Fangkui; Zhou Sheng; Dai Jian; Zhang Zhichao

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

机译：一种新的HSP70抑制剂，特异性靶向癌症相关的HSP70-BIM蛋白 - 蛋白质相互作用

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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-mu M binding affinity toward Hsp70 and selectively disrupted Hsp70-Bim PPI. The target specificity of S1g-6 in situ was validated by affinity-based protein profiling, coimmunoprecipitation, 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. (C) 2021 Elsevier Masson SAS. All rights reserved.

机译：靶向肿瘤相关的Hsp70 Bim蛋白-蛋白相互作用（PPI）为Hsp70抑制剂的设计提供了一种新策略。在此，我们基于已建立的BH3模拟物发现了一种新的Hsp70抑制剂S1g-6。S1g-6对Hsp70表现出亚μM结合亲和力，并选择性破坏Hsp70 Bim-PPI。通过基于亲和力的蛋白质分析、共免疫沉淀和基于细胞的shRNA分析，验证了S1g-6原位靶向特异性。S1g-6在招募Bim时特异性地对抗Hsp70的ATP酶活性，并通过抑制Hsp70的一些致癌客户在一些癌细胞系中显示出选择性凋亡诱导，代表了一类新的抗肿瘤候选细胞。Hsp70-Bim-PPI作为潜在的抗癌靶点显示出癌症依赖性作用。（c）2021爱思唯尔马松SAS。版权所有。

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《European Journal of Medicinal Chemistry: Chimie Therapeutique》 |2021年第1期|共10页
作者
Wang Ziqian; Song Ting; Guo Zongwei; Uwituze Laura B.; Guo Yafei; Zhang Hong; Wang Hang; Zhang Xiaodong; Pan Hao; Ji Tong; Yin Fangkui; Zhou Sheng; Dai Jian; Zhang Zhichao;
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作者单位

Dalian Univ Technol Zhang Dayu Sch Chem State Key Lab Fine Chem Dalian 116024 Liaoning Peoples;

Dalian Univ Technol Zhang Dayu Sch Chem State Key Lab Fine Chem Dalian 116024 Liaoning Peoples;

Dalian Univ Technol Sch Bioengn Dalian 116024 Liaoning Peoples R China;

Dalian Univ Technol Zhang Dayu Sch Chem State Key Lab Fine Chem Dalian 116024 Liaoning Peoples;

Dalian Univ Technol Sch Bioengn Dalian 116024 Liaoning Peoples R China;

Dalian Univ Technol Sch Bioengn Dalian 116024 Liaoning Peoples R China;

Dalian Univ Technol Sch Bioengn Dalian 116024 Liaoning Peoples R China;

Dalian Univ Technol Zhang Dayu Sch Chem State Key Lab Fine Chem Dalian 116024 Liaoning Peoples;

Dalian Univ Technol Zhang Dayu Sch Chem State Key Lab Fine Chem Dalian 116024 Liaoning Peoples;

Dalian Univ Technol Zhang Dayu Sch Chem State Key Lab Fine Chem Dalian 116024 Liaoning Peoples;

Dalian Univ Technol Zhang Dayu Sch Chem State Key Lab Fine Chem Dalian 116024 Liaoning Peoples;

Dalian Univ Technol Zhang Dayu Sch Chem State Key Lab Fine Chem Dalian 116024 Liaoning Peoples;

Dalian Univ Technol Zhang Dayu Sch Chem State Key Lab Fine Chem Dalian 116024 Liaoning Peoples;

Dalian Univ Technol Zhang Dayu Sch Chem State Key Lab Fine Chem Dalian 116024 Liaoning Peoples;

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正文语种 eng
中图分类药学;
关键词
Hsp70 inhibitor; Hsp70-bim PPI; Cancer-related target; Antitumor candidate;

机译：Hsp70抑制剂;Hsp70-bim-PPI;肿瘤相关靶点;抗肿瘤候选药物;

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9. Discovery of cancer-related new drug target proteins from re-constructed human disease network based on protein-protein interaction network [C] . Yoon Kyeong Lee, Hak Yong Kim IEEE International Conference on Bioinformatics and Biomedicine Workshop . 2009

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

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