A shape complementarity strategy based on NCA029 enables potent HsClpP agonists for the treatment of small cell lung carcinoma

  • Eur J Med Chem. 2025 Dec 5:299:118008. doi: 10.1016/j.ejmech.2025.118008.
Linjie Li  1 ,  Baozhu Luo  1 ,  Xudong Wang  2 ,  Zhongyu Jian  3 ,  Hong Liu  1 ,  Bo Ren  1 ,  Wenliang Qiao  4 ,  Youfu Luo  5 ,  Tao Yang  6
Affiliations
  • 1. Cancer Center and State Key Laboratory of Biotherapy, and Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3. State Key Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
  • 4. Department of Lung Cancer Center, Laboratory Lung Cancer, West China Hospital, West China Medical School, Sichuan University, Chengdu, China. Electronic address: [email protected].
  • 5. Cancer Center and State Key Laboratory of Biotherapy, and Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Mitor (Inner Mongolia) Pharmaceutical Co. Ltd, Hohho, 010090, China. Electronic address: [email protected].
  • 6. Cancer Center and State Key Laboratory of Biotherapy, and Laboratory of Human Diseases and Immunotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 40812068 DOI: 10.1016/j.ejmech.2025.118008
Abstract

Owing to its essential role in maintaining mitochondrial homeostasis, activation of HsClpP is potentially a promising strategy for treating a wide range of cancers, including small cell lung carcinoma (SCLC). In this work, by using a shape complementarity strategy, we designed and synthesized a series of HsClpP agonist based on NCA029, a non-imipridone HsClpP agonist identified in our previous work. Among these derivatives, compound 8o exhibited approximately 5-fold greater binding affinity than NCA029 with HsClpP due to attachment of an additional ring structure at the β-position of NCA029's double bond. It potently inhibited SCLC cells, such as H69 cells (8o: IC50 = 0.17 μM; NCA029: IC50 = 5.04 μM), and H82 cells (8o: IC50 = 0.19 μM; NCA029: IC50 = 1.04 μM). In addition, 8o exerted improved safety profiles than NCA029 in vitro and in vivo. Furthermore, compound 8o, which exhibits favorable pharmacokinetic properties, significantly inhibited tumor growth in non-SMC xenograft models, achieving a tumor growth inhibition rate of up to 63.01 %.

Keywords
HsClpP; Shape complementarity; Small cell lung carcinoma.
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