UT-59 is a specific inhibitor of cholesterol-sensing membrane protein Scap, binds to Scap's cholesterol-binding site, blocks SREBP activation and inhibits lipid synthesis.
UT-59 dramatically reduces mRNAs of target genes of SREBP1 (Insig-1, ACSS2, ACC1, FASN, SCD1) and SREBP-2 (HMG-CoA synthase, HMG-CoA reductase, LDL receptor, PCSK9, and others), reduces lipid synthesis.
UT-59 is not generally toxic to cells.
UT-59 binds to Scap and changes its conformation, promoting Scap's binding to Insig, which blocks ER-to-Golgi transport of Scap.
UT-59 selectively blocks Scap/SREBP transport without blocking the general process of ER-to-Golgi transport, and shows high specificity in competing for cholesterol binding to Scap's Loop1.
UT-59 can block SREBP processing in animals and sets the stage for testing the effects of specifically blocking the synthesis of fatty acids, triglycerides, and cholesterol in animal models of lipid dysregulation.
UT-59 is a promising candidate non-sterol small molecule that specifically suppresses the ER-to-Golgi transport of SREBPs in a manner similar to cholesterol.