2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Novel Activators of Human Caseinolytic Protease P with a Pyrazololactam Scaffold

Design, Synthesis, and Biological Evaluation of Novel Activators of Human Caseinolytic Protease P with a Pyrazololactam Scaffold

  • J Med Chem. 2025 May 22;68(10):9984-10007. doi: 10.1021/acs.jmedchem.4c03000.
Rui Tang 1,  Qiannan Li 2 3 4,  Heyang Zhou 5 6,  Yu Li 2 3 4,  Tong Li 1,  Jinxin Jiang 2 3 4,  Ziyuan Chen 2 3 4,  Lingmei Kong 5 6,  Yan Li 5 6,  Yibei Xiao 2 3 4,  Haiying Sun 1
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 4 Chongqing Innovation Institute of China Pharmaceutical University, Chongqing 401151, China.
  • 5 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan University, Kunming 650500, China.
  • 6 Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Yunnan University, Kunming 650500, China.
PMID: 40317731 DOI: 10.1021/acs.jmedchem.4c03000
Abstract

Based on D9, a previously reported small-molecule agonist of hClpP, a class of novel hClpP activators with a pyrazololactam scaffold was designed and synthesized. Detailed structure-activity relationship studies (SAR) for this class of compounds led to the identification of compound 24, which potently activated recombinant hClpP in a proteolysis assay with submicromolar potency and effectively inhibited cell growth in a broad panel of Cancer cell lines with IC50 values of 0.1-1 μM. Mechanism studies indicated that compound 24 can potently bind to cellular hClpP, effectively promote the formation of the hClpP tetradecamer, efficiently induce the degradation of hClpP substrates, robustly upregulate the expression of ATF4, and strongly induce Apoptosis in Molm13 and MDA-MB-231 cells. More importantly, compound 24 has promising PK and safety profiles, and showed potent antitumor activity in a murine MDA-MB-231 xenograft model.

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