SLC25A20 Inhibitors

Chemical inhibitors of SLC25A20 operate primarily by reducing the availability of substrates that SLC25A20 transports across the mitochondrial membrane. Triacsin C achieves this by inhibiting long-chain acyl-CoA synthetase, thereby reducing the synthesis of long-chain acyl-CoA molecules that serve as substrates for SLC25A20. Similarly, Perhexiline, Etomoxir, Oxfenicine, Vinclozolin, and Ranolazine inhibit carnitine palmitoyltransferase 1 (CPT1), a critical enzyme in the formation of acylcarnitines. This inhibition results in a lower pool of acylcarnitines, which correspondingly diminishes the substrate availability for SLC25A20, indirectly inhibiting its transport activity. Malonyl-CoA, a natural CPT1 inhibitor, similarly decreases the acylcarnitine levels available for SLC25A20 function. Through the inhibition of these enzymes, the intracellular concentration of acylcarnitines is kept low, which in turn limits the activity of SLC25A20 as it has fewer substrates to transport. The inhibition mechanism extends to other aspects of fatty acid metabolism that affect SLC25A20 indirectly. ST1326, a selective CPT2 inhibitor, increases the intramitochondrial acylcarnitine concentration, which may inhibit SLC25A20 through competitive inhibition or feedback mechanisms. Mildronate, by targeting gamma-butyrobetaine hydroxylase, leads to reduced carnitine and subsequently acylcarnitine levels, thus limiting the substrate availability for SLC25A20. Lastly, Sulfo-N-succinimidyl oleate inhibits fatty acid transport protein, which is expected to decrease intracellular fatty acid levels and in turn the acylcarnitine substrates necessary for SLC25A20's function.