Summary
Type 2 diabetes (T2D) is a world-wide epidemic with a medical need for additional targeted therapies. Suppression of hepatic glucose production (HGP) effectively ameliorates diabetes and can be exploited for its treatment. We hypothesized that targeting PGC-1α acetylation in liver, a chemical modification known to inhibit hepatic gluconeogenesis, could be potentially used for treatment of T2D. Thus, we designed a high-throughput chemical screen platform to quantify PGC-1α acetylation in cells and identified small molecules that increase PGC-1α acetylation, suppress gluconeogenic gene expression and reduce glucose production in hepatocytes. Based on the potency and bioavailability, we selected a small molecule, SR-18292, that reduces blood glucose, strongly increases hepatic insulin sensitivity and improves glucose homeostasis in dietary and genetic mouse models of T2D. These studies have important implications for understanding the regulatory mechanisms of glucose metabolism and treatment of T2D.
ERAP1 is an endoplasmic reticulum-resident zinc aminopeptidase
that plays an important role in the immune system by trimming peptides
for loading onto major histocompatibility complex proteins. Here,
we report discovery of the first inhibitors selective for ERAP1 over
its paralogues ERAP2 and IRAP. Compound 1 (N-(N-(2-(1H-indol-3-yl)ethyl)carbamimidoyl)-2,5-difluorobenzenesulfonamide)
and compound 2 (1-(1-(4-acetylpiperazine-1-carbonyl)cyclohexyl)-3-(p-tolyl)urea) are competitive inhibitors of ERAP1 aminopeptidase
activity. Compound 3 (4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic
acid) allosterically activates ERAP1’s hydrolysis of fluorogenic
and chromogenic amino acid substrates but competitively inhibits its
activity toward a nonamer peptide representative of physiological
substrates. Compounds 2 and 3 inhibit antigen
presentation in a cellular assay. Compound 3 displays
higher potency for an ERAP1 variant associated with increased risk
of autoimmune disease. These inhibitors provide mechanistic insights
into the determinants of specificity for ERAP1, ERAP2, and IRAP and
offer a new therapeutic approach of specifically inhibiting ERAP1
activity in vivo.
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