Discovery of a Potent and Oral Available Complex I OXPHOS Inhibitor That Abrogates Tumor Growth and Circumvents MEKi Resistance
- J Med Chem. 2023 May 11;66(9):6047-6069. doi: 10.1021/acs.jmedchem.2c01844.
- 1. Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.
- 2. Joint Center for Translational Medicine, Southern Medical University Affiliated Fengxian Hospital, Shanghai 201499, China.
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.