title: Discovery of a Selective Covalent Inhibitor of Lysophospholipase-like 1 (LYPLAL1) as a Tool to Evaluate the Role of this Serine Hydrolase in Metabolism.
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.
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Kay
authors.initials: K
authors.lastname: Ahn
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Markus
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Brown
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Calloway
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Ye
authors.initials: Y
authors.lastname: Che
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jinshan
authors.initials: J
authors.lastname: Chen
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Kimberly F
authors.initials: KF
authors.lastname: Fennell
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Kieran F
authors.initials: KF
authors.lastname: Geoghegan
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Gilbert
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jemy A
authors.initials: JA
authors.lastname: Gutierrez
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Adhiraj
authors.initials: A
authors.lastname: Lanba
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Chris
authors.initials: C
authors.lastname: Limberakis
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Magee
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Inish
authors.initials: I
authors.lastname: O'Doherty
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Oliver
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Brandon
authors.initials: B
authors.lastname: Pabst
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Parris
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Pfefferkorn
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Rolph
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Rushi
authors.initials: R
authors.lastname: Patel
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Brandon
authors.initials: B
authors.lastname: Schuff
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Veerabahu
authors.initials: V
authors.lastname: Shanmugasundaram
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jeremy T
authors.initials: JT
authors.lastname: Starr
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Varghese
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Vera
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Cecile
authors.initials: C
authors.lastname: Vernochet
authors.affiliation: Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc. , 610 Main Street, Cambridge, Massachusetts 02139, United States.|Worldwide Medicinal Chemistry and §Pharmacokinetics, Dynamics, & Metabolism, Pfizer Inc. , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Jiangli
authors.initials: J
authors.lastname: Yan
mesh_terms: D000818:Animals; D003460:Crystallization; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D008245:Lysophospholipase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012694:Serine / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D012694:Serine; D006867:Hydrolases; D008245:Lysophospholipase; C561408:LYPLAL1 protein, human