2. Academic Validation
  3. Structural Optimization of Pyrazole Compounds as Hsp90 Regulators with Enhanced Antitumor Activity

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-176404
    HSP90 Inhibitor
    HSP