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. 2013 Sep 16;4(11):1079-84.
doi: 10.1021/ml400275z. eCollection 2013 Nov 14.

Chemical Probe Identification Platform for Orphan GPCRs Using Focused Compound Screening: GPR39 as a Case Example

Markus Boehm  1 , David Hepworth  1 , Paula M Loria  2 , Lisa D Norquay  1 , Kevin J Filipski  1 , Janice E Chin  1 , Kimberly O Cameron  1 , Martin Brenner  1 , Peter Bonnette  1 , Shawn Cabral  1 , Edward Conn  1 , David C Ebner  1 , Denise Gautreau  1 , John Hadcock  1 , Esther C Y Lee  1 , Alan M Mathiowetz  1 , Michelle Morin  1 , Lucy Rogers  2 , Aaron Smith  1 , Maria VanVolkenburg  1 , Philip A Carpino  1
Affiliations

Chemical Probe Identification Platform for Orphan GPCRs Using Focused Compound Screening: GPR39 as a Case Example

Markus Boehm et al. ACS Med Chem Lett. .

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.

Keywords: GPCR-focused chemical library; GPR39; Orphan GPCRs; chemical probe identification platform.

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Figures

Figure 1
Figure 1
Design of GPCR-focused chemical library and compound subsets for screening.
Figure 2
Figure 2
GPR39 screening cascade in the orphan drug chemical probe identification platform.
Figure 3
Figure 3
Structure and pharmacological activities of GPR39 agonist 1 identified from oGPCR platform screening. Efficacies are relative to Zn2+ alone in the assays.
Figure 4
Figure 4
Treatment of 1 in HT29 cells in the presence and absence of siRNA constructs.
Figure 5
Figure 5
Effects of 1 and GLP1 control on human islet insulin secretion at low (2.8 mM) and stimulatory (11.2 mM) glucose (G) concentrations.
Figure 6
Figure 6
Structures and pharmacological activities of racemic 4, (+)-trans-5, and (−)-trans-5. Efficacies are relative to Zn2+ alone in the assays.
See this image and copyright information in PMC

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