Mubritinib

Mubritinib (TAK-165) is a selective inhibitor of the human epidermal growth factor receptor 2 (EGFR2; HER2), inhibiting HER2 phosphorylation with an IC50 value of 6nM. It is 4000-fold selective over EGFR, FGFR, PDGFR, JAK1, Src and Blk (IC50 > 25μM). Mubritinib inhibits the proliferation of breast, bladder, kidney and prostate cancer cells in vitro and in vivo. Mubritinib was shown to inhibit autophagy in a HER2-independent manner in cancer cells. Recently shown to be a mitochondrial electron transport chain complex I (NADH-CoQ reductase) inhibitor. Mubritinib functions through ubiquinone-dependent inhibition of electron transport chain (ETC) complex I activity and consequently oxidative phosphorylation (OXPHOS). This agent could be useful for immunometabolism research. Inhibition of electron transport chain in mitochondria leads to blocking of the transfer of electrons from iron-sulfur centers in complex I to ubiquinone. By inhibiting the mitochondrial respiratory complex I, this agent reduces cardiac-cell beat rate, with prolonged exposure resulting in cell death. Complex I inhibition is directly linked to anti-cancer cell activity.