Discovery and Characterization of a Nonacidic Small-Molecule Inhibitor of the Sodium-Coupled Dicarboxylate Transporter NaCT.

Citrate is a key metabolic intermediate that regulates both glycolysis and lipid metabolism. While most citrate is produced in mitochondria, some is imported from the bloodstream by the SLC13 family of sodium-coupled transporters. Among these, hepatic citrate transporter NaCT (SLC13A5) mediates citrate uptake and is a potential therapeutic target for metabolic disorders by limiting hepatic citrate uptake. However, the loss of NaCT expression or function is linked to neonatal encephalopathy and cancer risk, underscoring the need for selective tools to study NaCT biology. Here, we report the development of a potent and selective piperidinecarboxamide-based chemical probe, BI01383298, along with an inactive analog, BI01372674, and an alternative probe, BI01455810. BI01383298 is highly potent (IC50 = 25 nM), shows exceptional selectivity (>1000-fold over other SLC13 transporters), and has robust cellular activity, whereas BI01372674 shows no measurable activity. Together, these compounds provide valuable tools for probing the physiological and pathological roles of NaCT in metabolism and disease.