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Discovery of a Potent and Oral Available Complex I OXPHOS Inhibitor That Abrogates Tumor Growth and Circumvents MEKi Resistance.

Peng HeJuanjuan FengXinting XiaYue SunJia HeTian GuanYangrui PengXueli ZhangMingyao LiuXiufeng PangYihua Chen
Published in: Journal of medicinal chemistry (2023)
Targeting oxidative phosphorylation (OXPHOS) has emerged as a promising therapeutic strategy for cancer therapy. Here, we discovered a 1 H -1,2,3-triazole derivative HP661 as a highly potent and orally available OXPHOS inhibitor that effectively blocked the activity of mitochondrial complex I. HP661 specifically compromised the mitochondrial oxygen consumption of high-OXPHOS lung cancer cells but not that of low-OXPHOS lung cancer cells or normal cells in the low nanomolar range. Notably, mitogen-activated protein kinase kinase (MEK) inhibitor (trametinib)-resistant lung cancer cells with high levels of OXPHOS also showed marked sensitivity to HP661 , as indicated by decreased clonogenic growth and increased cell apoptosis upon treatment. In a mouse model of high-OXPHOS lung cancer, HP661 treatment not only significantly suppressed tumor growth but also augmented the therapeutic efficacy of trametinib by impairing tumor mitochondrial respiration. In summary, we identified HP661 as a highly effective OXPHOS inhibitor to abrogate the growth of high OXPHOS-dependent tumors and conquer high OXPHOS-mediated drug resistance.
Keyphrases
  • cancer therapy
  • oxidative stress
  • cell proliferation
  • induced apoptosis
  • drug delivery
  • cell cycle arrest
  • combination therapy