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.

热休克蛋白 90 (HSP90) 参与癌蛋白的稳定和活化，使其对致癌转化至关重要。然而，迄今为止评估的 HSP90 抑制剂并未在癌症治疗中产生预期的效果。在此，我们系统地描述了基于蛋白水解靶向嵌合体 (PROTAC) 策略的 HSP90 降解剂的设计、合成和评估。结果表明，候选化合物16b（BP3）可有效降解HSP90，有效抑制人乳腺癌细胞的生长。当用作单一药剂时，BP3可在小鼠中产生有效的肿瘤抑制作用。这些发现表明，我们的 HSP90 靶向 PROTAC 策略在乳腺癌治疗中具有潜在的新应用。