OPB-51602 / Otsuka - LARVOL DELTA

OXPHOS: A novel target for cancer therapy in oncogene addicted tumor (AACR 2018) - "...Here we report that oncogene addicted non-small cell lung carcinoma (NSCLC) cell line HCC827 and its gefitinib resistant clone and malignant melanoma cell line A375 and its vemurafanib resistant clone have significantly higher OXPHOS activity...Of note, significantly increased activity of STAT3 is detected in oncogene addicted cancer cells, and the increased mitochondrial oxygen consumption and complex I activity could be significantly inhibited by a novel small molecule inhibitor of STAT3, OPB-51602...Most importantly, the novel STAT3 inhibitor showed strong activity in three different murine models of carcinogenesis as well as in patients treated with the STAT3 inhibitor. These data provide evidence that oncogene addicted cancer cells switch to OXPHOS over glycolysis and serve as proof of principle for identifying targeted new OXPHOS inhibitor in recalcitrant cancers."

Melanoma • Non Small Cell Lung Cancer

STAT3 Inhibitor OPB-51602 Is Cytotoxic to Tumor Cells Through Inhibition of Complex I and ROS Induction. (PubMed, iScience) - "Cells undergoing reduced oxidative phosphorylation or expressing NDI1 NADH dehydrogenase from Saccharomyces cerevisiae, which bypasses mammalian complex I, were resistant to OPB-51602 toxicity. These results show that targeting mitochondrial STAT3 function causes synthetic lethality through complex I inhibition that could be exploited for cancer chemotherapy."

Journal • Immunology • Inflammation • Oncology • STAT3

Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance. (PubMed, Redox Biol) - "To that effect, we describe a novel OXPHOS targeting activity of the small molecule compound, OPB-51602 (OPB)...Collectively, we show here a switch to mitochondrial OXPHOS as a key driver of targeted drug resistance in oncogene-addicted cancers. This metabolic vulnerability is exploited by a novel OXPHOS inhibitor, which also shows promise in the clinical setting."

Journal