2. Academic Validation
  3. Discovery of Activators of Human Caseinolytic Protease P with a Benzolactam Scaffold

Discovery of Activators of Human Caseinolytic Protease P with a Benzolactam Scaffold

  • J Med Chem. 2026 Mar 12;69(5):6014-6037. doi: 10.1021/acs.jmedchem.5c03484.
Zhilong Li 1,  Ziyuan Chen 2 3 4,  Jiajun Luo 1,  Yuyang Wang 5 6,  Yiquan Jin 7,  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, School of Pharmacy, 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.
  • 7 School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
PMID: 41718714 DOI: 10.1021/acs.jmedchem.5c03484
Abstract

Based on compound 1, a previously identified activator of human caseinolytic protease P (hClpP) containing a pyrazololactam scaffold, a class of benzolactam derivatives was designed through a scaffold-hopping strategy. Structural optimization of this series led to the identification of LZL25, which potently activated recombinant hClpP with an EC50 of 0.36 μM and inhibited the growth of MDA-MB-231 cells with an IC50 of 0.29 μM. Mechanistic studies showed that LZL25 strongly bound to and activated cellular hClpP, effectively promoted the degradation of hClpP substrates in cells, and robustly induced Apoptosis in MDA-MB-231 cells. Further optimization yielded LZL50, which demonstrated favorable pharmacokinetic properties and exhibited potent antitumor activity in an MDA-MB-231 xenograft mouse model.

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