Complex I inhibitor OPB-111077 pairs with bendamustine to hit tumour metabolism
- OPB-111077, an oral first-in-class small molecule, inhibits mitochondrial Complex I and suppresses oxidative phosphorylation.
- It showed anti-tumour activity across haematological and solid tumour cell lines, cell-line xenografts and lymphoma patient-derived xenografts.
- Bendamustine pushed cancer cells toward an oxidative-phosphorylation-dependent state, which made them more sensitive to the inhibitor.
- The combination was synergistic, shutting down both oxidative phosphorylation and glycolysis.
💡 Points Based on the abstract
Complex I inhibitors have a hard history: on-target neurotoxicity and lactic acidosis narrowed the window in the clinic, so synergy in xenografts says little until we see exposure at the combination dose. The bendamustine-induced OXPHOS dependence is the interesting hook, but I'd want a rescue control (e.g. a yeast NDI1 bypass) to prove the effect is truly Complex I, plus tolerability data for the pair.