Abstract 4053: NGY-B is a novel inhibitor of MCT transporters blocking lactate and glucose metabolisms

Abstract

Abstract Aberrant glycolytic flux and mitochondrial respiration are known to drive tumor progression and metastasis. Therefore, targeting metabolic alterations in cancer is critical for developing novel cancer therapeutics. We have developed NGY-B as a first-in-Class small molecule inhibitor of the lactate transporters, MCT1 and MCT4, that also decreases mitochondrial respiration. These transporters play a crucial role in regulating both glycolysis and oxidative phosphorylation in cancer cells. NGY-B treatment exhibited potent in vitro cytotoxicity in cancer cells with various levels of MCT1 and MCT4 expression. The on-target activity of NGY-B was validated by measuring intracellular and extracellular lactate levels. NGY-B blocks lactate import through MCT1 under high lactate conditions and lactate export through MCT4 in high glucose conditions. Seahorse and U-13C-glucose tracing analysis demonstrated NGY-B treatment modulates glycolysis and oxidative phosphorylation consistent with the lactate measurement data. Therefore, NGY-B is a novel inhibitor of MCT1/4 while also exhibiting inhibition of mitochondrial respiration. Citation Format: Sambad Sharma, Gregory Goreczny, Nicole Bowman, Jennifer Duffy, Daliya Banerjee, Sanath Wijerathna, John Dzuris, Jaime Escobedo, Vincent Sandanayaka. NGY-B is a novel inhibitor of MCT transporters blocking lactate and glucose metabolisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4053.