2. Academic Validation
  3. Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma

Selective activator of human ClpP triggers cell cycle arrest to inhibit lung squamous cell carcinoma

  • Nat Commun. 2023 Nov 3;14(1):7069. doi: 10.1038/s41467-023-42784-4.
Lin-Lin Zhou # 1 2,  Tao Zhang # 1,  Yun Xue # 3 4,  Chuan Yue 1 5,  Yihui Pan 2 6,  Pengyu Wang 6,  Teng Yang 1 6,  Meixia Li 7,  Hu Zhou 2 6 8,  Kan Ding 2 7,  Jianhua Gan 9,  Hongbin Ji 10 11 12,  Cai-Guang Yang 13 14 15 16
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, 100049, Beijing, China.
  • 3 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 4 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 5 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
  • 7 Carbohydrate-Based Drug Research Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 8 Analytical Research Center for Organic and Biological Molecules, State Key Laboratory of Drug Research, Shanghai Institute of Materia Media, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 9 School of Life Sciences, Fudan University, Shanghai, 200433, China.
  • 10 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, 200031, China. [email protected].
  • 11 School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. [email protected].
  • 12 School of Life Science and Technology, Shanghai Tech University, Shanghai, 200120, China. [email protected].
  • 13 State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 14 University of Chinese Academy of Sciences, 100049, Beijing, China. [email protected].
  • 15 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China. [email protected].
  • 16 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China. [email protected].
  • # Contributed equally.
PMID: 37923710 DOI: 10.1038/s41467-023-42784-4
Abstract

Chemo-activation of mitochondrial ClpP exhibits promising Anticancer properties. However, we are currently unaware of any studies using selective and potent ClpP activators in lung squamous cell carcinoma. In this work, we report on such an activator, ZK53, which exhibits therapeutic effects on lung squamous cell carcinoma in vivo. The crystal structure of ZK53/ClpP complex reveals a π-π stacking effect that is essential for ligand binding selectively to the mitochondrial ClpP. ZK53 features on a simple scaffold, which is distinct from the activators with rigid scaffolds, such as acyldepsipeptides and imipridones. ZK53 treatment causes a decrease of the electron transport chain in a ClpP-dependent manner, which results in declined oxidative phosphorylation and ATP production in lung tumor cells. Mechanistically, ZK53 inhibits the adenoviral early region 2 binding factor targets and activates the ataxia-telangiectasia mutated-mediated DNA damage response, eventually triggering cell cycle arrest. Lastly, ZK53 exhibits therapeutic effects on lung squamous cell carcinoma cells in xenograft and autochthonous mouse models.

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