Discovery of BP3 as an efficacious proteolysis targeting chimera (PROTAC) degrader of HSP90 for treating breast cancer

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. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

This study systematically described the design, synthesis, and evaluation of HSP90 degraders based on the PROTAC strategy. The candidate compound 16b (BP3) was found to effectively degrade HSP90 and inhibit the growth of human breast cancer cells. The results suggest that the HSP90-targeting PROTAC strategy has potential novel applications in breast cancer therapy.