Discovery of Selective Small Molecule Inhibitors of Monoacylglycerol Acyltransferase 3

Inhibition of triacylglycerol (TAG)
biosynthetic enzymes has been
suggested as a promising strategy to treat insulin resistance, diabetes,
dyslipidemia, and hepatic steatosis. Monoacylglycerol acyltransferase
3 (MGAT3) is an integral membrane enzyme that catalyzes the acylation
of both monoacylglycerol (MAG) and diacylglycerol (DAG) to generate
DAG and TAG, respectively. Herein, we report the discovery and characterization
of the first selective small molecule inhibitors of MGAT3. Isoindoline-5-sulfonamide
(6f, PF-06471553) selectively inhibits MGAT3 with high
in vitro potency and cell efficacy. Because the gene encoding MGAT3
(MOGAT3) is found only in higher mammals and humans,
but not in rodents, a transgenic mouse model expressing the complete
human MOGAT3 was used to characterize the effects
of 6f in vivo. In the presence of a combination of diacylglycerol
acyltransferases 1 and 2 (DGAT1 and DGAT2) inhibitors, an oral administration
of 6f exhibited inhibition of the incorporation of deuterium-labeled
glycerol into TAG in this mouse model. The availability of a potent
and selective chemical tool and a humanized mouse model described
in this report should facilitate further dissection of the physiological
function of MGAT3 and its role in lipid homeostasis.