AR-C155858 is a potent and selective inhibitor of monocarboxylate transporters MCT1 and MCT2 with Ki values of 2.3nM and less than 10 nM, respectively [1].
MCT is a monocarboxylate transporter family with 14 members. Among these transporters, MCT1 and MCT2 are worked for the uptake and efflux of lactic acid. As a selective inhibitor of MCT1 and MCT2, AR-C155858 can be used to probe MCTs’ roles in the metabolic studies. Besides that, AR-C155858 was found to have immunosuppressive activity and can inhibit the proliferation of T-lymphocytes. The binding site of MCT1 for AR-C155858 contains transmembrane helices 7-10 in C-terminal domain. The two residues Phe360 and Ser364 play important roles in the binding [1 and 2].
In rat erythrocytes in which the AE1 mediated lactate transport had been blocked, AR-C155858 inhibited endogenous MCT1 mediated L-lactate uptake dose-dependently. AR-C155858 showed to be a tight-binding non-competitive inhibitor with Ki value of 2.3±1.4 nM and Kcat value of 12.2±1.1 s-1.In Xenopus oocytes expressing MCT1, MCT2 or MCT4, AR-C155858 at concentration of 100 nM showed 100% inhibition of MCT1 mediated lactate uptake. For MCT2, AR-C155858 at 10 nM showed 70% inhibition. AR-C155858 had no significant effect against MCT4 even at concentration up to 10 μM. In addition, it has been found that the inhibition of MCTs caused by AR-C155858 can be affected by the co-expression of ancillary proteins. The presence of embigin reduced the sensitivity of MCT2 against AR-C155858’s inhibition. AR-C155858 potently suppressed the uptake of lactic acid in Ras-transformed fibroblast CCL39 cells via inhibiting MCT1 and MCT2 but no MCT4. The suppression subsequently resulted in significant decrease of glycolysis [1, 3 and 4].
In nude mice implanted with Ras-transformed CCL39 fibroblasts, the administration of AR-C155858 at dose of 30 mg/kg twice daily resulted in significant tumor growth suppression [4].
References:
[1] Ovens MJ, Davies AJ, Wilson MC, Murray CM, Halestrap AP. AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7-10. Biochem J. 2010 Jan 15;425(3):523-30.
[2] Nancolas B, Sessions RB, Halestrap AP. Identification of key binding site residues of MCT1 for AR-C155858 reveals the molecular basis of its isoform selectivity. Biochem J. 2015 Feb 15;466(1):177-88.
[3] Ovens MJ, Manoharan C, Wilson MC, Murray CM, Halestrap AP. The inhibition of monocarboxylate transporter 2 (MCT2) by AR-C155858 is modulated by the associated ancillary protein. Biochem J. 2010 Oct 15;431(2):217-25.
[4] Le Floch R, Chiche J, Marchiq I, Naiken T, Ilc K, Murray CM, Critchlow SE, Roux D, Simon MP, Pouysségur J. CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16663-8.
