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

  • J Med Chem. 2025 May 22;68(10):9886-9905. doi: 10.1021/acs.jmedchem.4c02182.
Zi-Wen Feng  1  2 ,  Li Li  1  2  3 ,  Shi-Duo Zhang  1  2 ,  Ying-Ji Wang  4 ,  Jia-Yue Pei  1  2 ,  Nan-Nan Chen  1  2 ,  Bei-Duo Wu  1  2 ,  Qiu-Ling Zheng  4 ,  Qi-Dong You  1  2 ,  Xiao-Ke Guo  1  2 ,  Xiao-Li Xu  1  2
Affiliations
  • 1. Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 3. School of Pharmacy, Jiangsu Health Vocational College, Nanjing 210029, China.
  • 4. Department of Pharmaceutical Analysis, College of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
PMID: 40310691 DOI: 10.1021/acs.jmedchem.4c02182
Abstract

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.

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