title: Chemical Probe Identification Platform for Orphan GPCRs Using Focused Compound Screening: GPR39 as a Case Example.
abstract: Orphan G protein-coupled receptors (oGPCRs) are a class of integral membrane proteins for which endogenous ligands or transmitters have not yet been discovered. Transgenic animal technologies have uncovered potential roles for many of these oGPCRs, providing new targets for the treatment of various diseases. Understanding signaling pathways of oGPCRs and validating these receptors as potential drug targets requires the identification of chemical probe compounds to be used in place of endogenous ligands to interrogate these receptors. A novel chemical probe identification platform was created in which GPCR-focused libraries were screened against sets of oGPCR targets, with a goal of discovering fit-for-purpose chemical probes for the more druggable members of the set. Application of the platform to a set of oGPCRs resulted in the discovery of the first reported small molecule agonists for GPR39, a receptor implicated in the regulation of insulin secretion and preservation of beta cells in the pancreas. Compound 1 stimulated intracellular calcium mobilization in recombinant and native cells in a GPR39-specific manner but did not potentiate glucose-stimulated insulin secretion in human islet preparations.
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Markus
authors.initials: M
authors.lastname: Boehm
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: David
authors.initials: D
authors.lastname: Hepworth
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism-New Chemical Entities, Primary Pharmacology Group, Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Loria
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Norquay
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Janice E
authors.initials: JE
authors.lastname: Chin
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Kimberly O
authors.initials: KO
authors.lastname: Cameron
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Martin
authors.initials: M
authors.lastname: Brenner
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Bonnette
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Shawn
authors.initials: S
authors.lastname: Cabral
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Edward
authors.initials: E
authors.lastname: Conn
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: David C
authors.initials: DC
authors.lastname: Ebner
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Denise
authors.initials: D
authors.lastname: Gautreau
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: John
authors.initials: J
authors.lastname: Hadcock
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Esther C Y
authors.initials: EC
authors.lastname: Lee
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Mathiowetz
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Michelle
authors.initials: M
authors.lastname: Morin
authors.affiliation: Department of Pharmacokinetics, Dynamics and Metabolism-New Chemical Entities, Primary Pharmacology Group, Pfizer Worldwide Research and Development , Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Lucy
authors.initials: L
authors.lastname: Rogers
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Smith
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: VanVolkenburg
authors.affiliation: Departments of Cardiovascular, Metabolic and Endocrine Diseases and Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Pfizer Worldwide Research and Development , 620 Memorial Drive, Cambridge, Massachusetts 02139, United States.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Carpino
keywords: GPCR-focused chemical library; GPR39; Orphan GPCRs; chemical probe identification platform