Development of novel MOG analogues with increased stability to explore MCT2 and α-ketoglutarate biology in vivo

Abstract

ABSTRACTα-ketoglutarate (αKG) is a central metabolic node with far-reaching influence on cellular physiology. The αKG analogue N-oxalylglycine (NOG) and its membrane-permeable pro-drug derivative dimethyloxalylglycine (DMOG) have been broadly used as tool compounds both in vitro and in vivo to study αKG-dependent processes. In cell culture media, DMOG is rapidly converted to MOG, a substrate of the monocarboxylate transporter MCT2. The expression level of MCT2 determines the intracellular concentration of NOG, and, as such, influences the molecular targets NOG engages with. Here we show that DMOG and MOG are highly unstable also in mouse blood. We therefore designed and characterised a series of MOG analogues with two aims: to improve pharmacokinetic properties, and to explore the pharmacophore of MCT2, a relatively understudied member of the SLC16 family. We report MOG analogues that maintain MCT2-dependent uptake, including NOG-generating compounds that replicate the metabolic effects of MOG in a concentration-dependent manner. One such analogue, IPOG, shows significantly increased blood stability, and an improved overall pharmacokinetic profile, leading to increased NOG accumulation in MCT2-expressing tumours versus isogenic controls.