2. Academic Validation
  3. Discovery of a Selective Covalent Inhibitor of Lysophospholipase-like 1 (LYPLAL1) as a Tool to Evaluate the Role of this Serine Hydrolase in Metabolism

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

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.
PMID: 27391855 DOI: 10.1021/acschembio.6b00266
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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