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Heat shock protein 90 (Hsp90), a highly conserved and widely expressed molecular chaperone, is mainly responsible for maintaining the correct folding of client proteins and is closely related to the stability and activation of tumour-related proteins. Hsp90α, the major isoform of Hsp90, can promote tumour cell migration and metastasis, and is abundantly secreted in highly invasive tumours. To date, most pan-Hsp90 inhibitors have been limited in their applications due to high toxicity. Herein, we described the candidate compound X10g based on a proteolysis-targeting chimaera (PROTAC) strategy that potently and selectively degraded Hsp90α. The results showed that X10g inhibited tumours better with lower toxicity in vivo. These findings demonstrate that synthesized selective Hsp90α degrader X10g provides a new strategy for breast cancer therapy. [Display omitted] • Designed and synthesized a series of PROTACs that selectively targeted Hsp90α. • X10g was found to selectively degrade Hsp90α without affecting Hsp90β. • X10g showed antitumour activity in vivo and had no significant effect on the body weights of mice. [ABSTRACT FROM AUTHOR]

Heat shock protein 90 (HSP90) is involved in the stabilization and activation of oncoproteins, rendering it essential for oncogenic transformation. However, the HSP90 inhibitors evaluated to date have not led to the expected effects in cancer therapy. Herein, we systematically described the design, synthesis, and evaluation of HSP90 degraders based upon the proteolysis-targeting chimera (PROTAC) strategy. The results showed that the candidate compound 16b (BP3) potently degraded HSP90 and effectively inhibited the growth of human breast cancer cells. When used as a single agent, BP3 led to effective tumor suppression in mice. These findings demonstrate that our HSP90-targeting PROTAC strategy has potential novel applications in breast cancer therapy. [Display omitted] • A series of PROTACs targeting HSP90 were designed for the first time and subsequently synthesized. • BP3 had a certain degradation effect on HSP90 protein in MCF-7 cells. • BP3 had a significant inhibition of breast cancer cells in vitro or in vivo compared with control. [ABSTRACT FROM AUTHOR]