Discovery of a Selective Covalent Inhibitor of Lysophospholipase-like 1 (LYPLAL1) as a Tool to Evaluate the Role of this Serine Hydrolase in Metabolism
- ACS Chem Biol. 2016 Sep 16;11(9):2529-40. doi: 10.1021/acschembio.6b00266.
- 1. Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.
- 2. Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
Lysophospholipase-like 1 (LYPLAL1) is an uncharacterized metabolic serine hydrolase. Human genome-wide association studies link variants of the gene encoding this enzyme to fat distribution, waist-to-hip ratio, and nonalcoholic fatty liver disease. We describe the discovery of potent and selective covalent small-molecule inhibitors of LYPLAL1 and their use to investigate its role in hepatic metabolism. In hepatocytes, selective inhibition of LYPLAL1 increased glucose production supporting the inference that LYPLAL1 is a significant actor in hepatic metabolism. The results provide an example of how a selective chemical tool can contribute to evaluating a hypothetical target for therapeutic intervention, even in the absence of complete biochemical characterization.
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Cat. No.Product NameDescriptionTargetResearch Area
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Research Areas: Metabolic Disease