Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 66, Issue 9, Pages 6047-6069Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01844
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HP661 is a highly effective OXPHOS inhibitor that can inhibit mitochondrial oxygen consumption in high OXPHOS lung cancer cells. It also shows significant sensitivity in MEK inhibitor-resistant lung cancer cells and has therapeutic efficacy against high OXPHOS lung cancer.
Targeting oxidative phosphorylation (OXPHOS) has emerged as a promising therapeutic strategy for cancer therapy. Here, we discovered a 1H-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.
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