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

Lin-Lin Zhou, Tao Zhang, Yun Xue, Chuan Yue, Yihui Pan, Pengyu Wang, Teng Yang, Meixia Li, Hu Zhou, Kan Ding, Jianhua Gan, Hongbin Ji () and Cai-Guang Yang ()
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Lin-Lin Zhou: State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Tao Zhang: State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Yun Xue: State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
Chuan Yue: State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Yihui Pan: University of Chinese Academy of Sciences
Pengyu Wang: University of Chinese Academy of Sciences
Teng Yang: State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Meixia Li: 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
Hu Zhou: University of Chinese Academy of Sciences
Kan Ding: University of Chinese Academy of Sciences
Jianhua Gan: Fudan University
Hongbin Ji: State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
Cai-Guang Yang: State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42784-4

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