Discovery of a Potent and Oral Available Complex I OXPHOS Inhibitor That Abrogates Tumor Growth and Circumvents MEKi Resistance
Peng He, Juanjuan Feng, Xinting Xia, Yue Sun, Jia He, Tian Guan, Yangrui Peng, Xueli Zhang, Mingyao Liu, Xiufeng Pang, Yihua Chen
Abstract
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.