Discovery of Potent Inhibitors Against GPAT (Glycerol 3-Phosphate Acyltransferase) for Treatment of Cancer and Other Diseases

Feng Jin

Obesity is a common social healthy focus, and about 66% American adults suffer this disease, which leads to a series of subsequent diseases, including diabetes, hypertension, cardiovascular diseases, non-alcoholic fatty liver disease, even certain types of cancer. Glycerol-3-phosphate acyltrans-ferase-1 (mtGPAT) catalyzes the following key step in the synthesis of animal fat and plays a central role in the biological process of obesity.

A diagram illustrating the rate-limiting step of glycerolipid biosynthesis. Top Section: Contains a chemical equation showing glycerol-3-phosphate (a molecule with three hydroxyl groups and a phosphate group) combined with long-chain acyl-CoAs, resulting in lysophosphatidic acid. The enzyme GPAT 1 is indicated beside the arrow leading to lysophosphatidic acid, which features several functional groups and a sodium ion. Bottom Section: Displays triacylglycerol and glycerol structures, indicating a transformation process labeled "esterified," leading to phosphatidic acid (which has a phosphate group and hydroxyl groups). The entire diagram represents crucial reactions involved in the biosynthesis of glycerolipids.
Scheme 1. Biological synthesis of TAG

Increased triacylglycerol(TAG) synthesis is associate with obesity and many other health problems, thus GPAT has been supported as a good target for anti-obesity treatment. However, to date, no GAPT inhibitor has been approved for clinical trials maybe due to moderate or weak inhibitory activity against GPAT. And FSG67, a GPAT inhibitor, was initiated as an anti-obesity reagent. In our precious study, we discovered FSG67 has good in vivo anticancer activity, but still with some biological shortcomings, for example, an in vitro µM anti-GPAT capacity. So further we design a series of new and potent GPAT inhibitors, of which some representative compounds may be appropriate for further clinical development.

A diagram depicting two sections related to chemical structures and modifications. Section A (top): Shows a reaction involving an organic molecule featuring three amino acids: arginine (Arg), lysine (Lys), and histidine (His). The molecule is shown with a phosphate group and a long-chain acyl group (C₁₆H₃₃) connected to the sulfur of CoA, labeled as SCₒA. Section B (bottom): Displays a similar structure with the same amino acids (Arg, Lys, His) and includes a sulfur bond to a nitrogen atom in a saturated chain connected to a phenyl group (represented as a benzene-like structure). Below the structure, an explanation provides options for X, where X can represent different groups, such as -CH₂PO₂⁻, -PO₂⁻, or -CO. Section b (right): Illustrates a simplified chemical structure with labeled variables (X, Y, Z) and notes about a compound named FSG67, specifying that X is o-COOH, Z is Ph (phenyl), and Y is NH₂SO₂R. The image highlights important chemical components and potential reactions in biochemical processes.
Scheme 2. a) Substrate-based design strategy; b) Mimic compounds, are capable of competing with A, and block the synthesis of TAG.