The disruption of protein-protein interactions with co-chaperones and client substrates as a strategy towards Hsp90 inhibition

• 作者: Michael A.Serwetnyk Brian S.J.Blagg
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（6）
• 所属期刊栏目: Reviews
• 页码范围: 1446-1468
• 页数: 23页
• 语种: 英文

摘要

The 90-kiloDalton (kD) heat shock protein (Hsp90) is a ubiquitous,ATP-dependent molec-ular chaperone whose primary function is to ensure the proper folding of several hundred client protein substrates.Because many of these clients are overexpressed or become mutated during cancer progres-sion,Hsp90 inhibition has been pursued as a potential strategy for cancer as one can target multiple on-coproteins and signaling pathways simultaneously.The first discovered Hsp90 inhibitors,geldanamycin and radicicol,function by competitively binding to Hsp90's N-terminal binding site and inhibiting its ATPase activity.However,most of these N-terminal inhibitors exhibited detrimental activities during clinical evaluation due to induction of the pro-survival heat shock response as well as poor selectivity amongst the four isoforms.Consequently,alternative approaches to Hsp90 inhibition have been pursued and include C-terminal inhibition,isoform-selective inhibition,and the disruption of Hsp90 protein-protein interactions.Since the Hsp90 protein folding cycle requires the assembly of Hsp90 into a large heteroprotein complex,along with various co-chaperones and immunophilins,the development of small molecules that prevent assembly of the complex offers an alternative method of Hsp90 inhibition.