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.
Kay Ahn  1  2 Markus Boehm  1  2 Matthew F Brown  1  2 Jessica Calloway  1  2 Ye Che  1  2 Jinshan Chen  1  2 Kimberly F Fennell  1  2 Kieran F Geoghegan  1  2 Adam M Gilbert  1  2 Jemy A Gutierrez  1  2 Amit S Kalgutkar  1  2 Adhiraj Lanba  1  2 Chris Limberakis  1  2 Thomas V Magee  1  2 Inish O'Doherty  1  2 Robert Oliver  1  2 Brandon Pabst  1  2 Jayvardhan Pandit  1  2 Kevin Parris  1  2 Jeffrey A Pfefferkorn  1  2 Timothy P Rolph  1  2 Rushi Patel  1  2 Brandon Schuff  1  2 Veerabahu Shanmugasundaram  1  2 Jeremy T Starr  1  2 Alison H Varghese  1  2 Nicholas B Vera  1  2 Cecile Vernochet  1  2 Jiangli Yan  1  2
Affiliations
  • 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.
Abstract

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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