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Updated: Jul 11, 2025

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

Lin-Lin Zhou1,2, Tao Zhang1, Yun Xue3,4

  • 1State Key Laboratory of Drug Research, Centre for Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Nature Communications
|November 4, 2023
PubMed

Insights

A novel compound, ZK53, selectively activates mitochondrial ClpP, offering a new therapeutic strategy for lung squamous cell carcinoma. This activator demonstrates in vivo efficacy by disrupting tumor cell energy production and inducing DNA damage.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Mitochondrial ClpP activation shows anticancer potential.
  • Selective and potent ClpP activators for lung squamous cell carcinoma are needed.

Purpose of the Study:

  • To identify and characterize a novel, selective ClpP activator for lung squamous cell carcinoma.
  • To investigate the therapeutic effects and underlying mechanisms of ZK53 in lung squamous cell carcinoma.

Main Methods:

  • Crystal structure analysis of the ZK53/ClpP complex.
  • In vitro assays measuring electron transport chain activity, oxidative phosphorylation, and ATP production.
  • In vivo studies using xenograft and autochthonous mouse models of lung squamous cell carcinoma.
  • Analysis of ZK53's impact on adenoviral early region 2 binding factor and ataxia-telangiectasia mutated-mediated DNA damage response.

Main Results:

  • ZK53 selectively binds to mitochondrial ClpP via a π-π stacking interaction.
  • ZK53 treatment reduces electron transport chain activity, oxidative phosphorylation, and ATP production in lung tumor cells.
  • ZK53 inhibits adenoviral early region 2 binding factor targets and activates ATM-mediated DNA damage response, leading to cell cycle arrest.
  • ZK53 demonstrates therapeutic efficacy in preclinical lung squamous cell carcinoma models.

Conclusions:

  • ZK53 is a potent and selective activator of mitochondrial ClpP with a distinct scaffold.
  • ZK53 exerts anticancer effects by disrupting cellular energy metabolism and inducing DNA damage response.
  • ZK53 represents a promising therapeutic agent for lung squamous cell carcinoma.

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