An inhibitor of the mitochondrial respiratory chain exerts synergistic anti‐tumour effects when combined with alkylating agents

Background and Purpose Cancer cells exhibit the Warburg effect, but oxidative phosphorylation (OXPHOS) is also important for cancer cell proliferation. Metabolic reprogramming from glycolysis to OXPHOS is one mechanism of resistance to anti‐tumour drugs. Here, we have synthesized and characterized OPB‐111077, a novel, first‐in‐class orally available small‐molecule compound, and investigated its anti‐tumour activity and therapeutic potential in combination with alkylating agents. Experimental Approach Inhibition of mitochondrial function by OPB‐111077 were assessed by measuring the oxygen consumption rate, ATP production and Complex I enzymatic activity. anti‐tumour effects were evaluated in human haematological and solid tumour cell lines and in cell line‐derived xenograft and lymphoma patient‐derived xenograft models. Mechanistic studies included CRISPR screening, metabolomic analyses, and measurements of the oxygen consumption and extracellular acidification rates. Effects of OPB‐111077 combined with alkylating agents were also assessed in mice. Key Results OPB‐111077 inhibited mitochondrial respiratory chain Complex I, suppressed OXPHOS, and exerted anti‐tumour effects in several models. OPB‐111077 demonstrated synergism with the alkylating agent bendamustine, with simultaneous inhibition of both OXPHOS and glycolysis. Bendamustine reprogrammed cancer cells into an OXPHOS‐dominant state, thereby enhancing the efficacy of OPB‐111077. Conclusion and Implications Based on these findings, we propose a novel anticancer therapeutic strategy of combining OXPHOS inhibitors with alkylating agents. OPB‐111077 has demonstrated potential in combination therapy and was recently evaluated with bendamustine and rituximab in a Phase 1 clinical trial for patients with relapsed/refractory diffuse large B‐cell lymphoma (NCT04049825).