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

This is the authors' abstract. We don't add key points for this paper.

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 39 ( DDO-6691 ) 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 39 (IC 50 > 50 μM) compared to their Cdc37-knockout counterparts. Importantly, compound 39 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.