HP661

HP661 is an inhibitor of mitochondrial complex I, also known as NADH dehydrogenase.¹ It is selective for complex I, inhibiting it by 77.6%, over complex III, which it inhibits by 28.1%, and complexes II and IV, which it does not inhibit, at 1 µM. HP661 selectively reduces viability of the human lung cancer cells H460, NCI H441, and trametinib-resistant A549 cells (IC₅₀s = 10.6, 29.7, and 15.1 nM, respectively), which all have high levels of oxidative phosphorylation, over NCI H358 human lung cancer cells (IC₅₀ = >10,000 nM), which have low levels of oxidative phosphorylation, and non-cancerous human pancreatic normal epithelial (HPNE) and MRC-5 human fetal lung fibroblast cells (IC₅₀s = >10,000 nM for both). HP661 reduces tumor volume in an H460 mouse xenograft model when administered at a dose of 30 mg/kg twice per day and has an additive effect on trametinib-induced reduction of tumor growth.

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1. He, P., Feng, J., Xia, X., et al. Discovery of a potent and oral available complex I OXPHOS inhibitor that abrogates tumor growth and circumvents MEKi resistance. J. Med. Chem. 66(9), 6047-6069 (2023).