FABP12 Inhibitors

Chemical inhibitors of FABP12 act by directly or indirectly preventing the protein's ability to bind and transport fatty acids, essential for its biological function. Orlistat, a lipase inhibitor, reduces the breakdown of fats, which limits the availability of free fatty acids for FABP12, leading to functional inhibition as the protein cannot operate without its substrates. Similarly, Triacsin C and Etomoxir target enzymes upstream of FABP12's function-long-chain acyl-CoA synthetase and carnitine palmitoyltransferase 1 (CPT1), respectively. By inhibiting these enzymes, both chemicals decrease the production or utilization of acyl-CoA and fatty acids, thus depriving FABP12 of necessary substrates. Perhexiline also inhibits CPT1 but through a different mechanism that leads to an increase in cytosolic fatty acid concentration, potentially saturating FABP12 and impairing its transport function by overwhelming the protein with an excess of ligands.

In a similar vein, Sulfo-N-succinimidyl oleate (SSO) inhibits the transport of fatty acids into cells, which would reduce the intracellular concentration of fatty acids available for FABP12 to bind. This lack of substrate availability can directly lead to the functional inhibition of FABP12. Cerulenin, by hindering fatty acid synthase, similarly cuts down the endogenous supply of fatty acids, which are crucial for FABP12's functioning. TTA and GSK2194069 both disrupt fatty acid metabolism but at different points. TTA inhibits mitochondrial fatty acid oxidation, while GSK2194069 inhibits fatty acid synthase, both resulting in altered fatty acid levels that can lead to FABP12 inhibition through substrate imbalance. BMS-309403 acts more directly, as it competes with natural fatty acid ligands of FABP12 by binding to its fatty acid pocket, which could prevent FABP12 from binding its natural substrates. PF-06424439, a diacylglycerol acyltransferase inhibitor, reduces triglyceride synthesis, which can lead to a relative increase in free fatty acid levels, potentially saturating FABP12 with excess ligands and thus inhibiting its function. A-967079 and MK-886, inhibit fatty acid amide hydrolase and 5-lipoxygenase-activating protein, respectively, causing shifts in the cellular balance of fatty acids and their derivatives that may indirectly inhibit FABP12 by changing the availability or composition of its ligands.