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 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 (IC50 > 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.