Structural Optimization of Pyrazole Compounds as Hsp90 Regulators with Enhanced Antitumor Activity.

Targeting Hsp90 is an effective strategy for cancer therapy. TAS-116 has been approved for the treatment of gastrointestinal stromal tumors. Our previous studies identified a series of pyrazole derivatives as covalent Hsp90 inhibitors that allosterically disrupt the Hsp90-Cdc37 interaction. Here, through systematic structure-activity relationship (SAR) optimization, compound () with a new covalent warhead was developed, which demonstrates improved ADME properties and significantly enhanced antitumor activity. Notably, parental HCT-116 cells exhibited markedly greater sensitivity to compound (IC > 50 μM) compared to their Cdc37-knockout counterparts. Importantly, compound displayed potent tumor growth inhibition in HCT-116 xenograft mouse models. These collective findings underscore the therapeutic promise of covalent Hsp90-targeted disruption of the Hsp90-Cdc37 complex, offering a novel mechanistic approach to cancer treatment.