Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

In this study, we identified two previously described kinase inhibitors—3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(3-methyl-1H-pyrazol-5-yl)-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine (LY2784544) and 1H-benzimidazole-4-carboxylic acid, 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-...

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Bibliographic Details
Published in:Molecular pharmacology 2016-12, Vol.90 (6), p.726-737
Main Authors: Sato, Seiji, Huang, Xi-Ping, Kroeze, Wesley K., Roth, Bryan L.
Format: Article
Language:English
Subjects:
Allosteric Regulation - drug effects
beta-Arrestins - metabolism
Cell Line
Cyclic AMP - metabolism
Drug Discovery
Drug Evaluation, Preclinical
GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism
GTP-Binding Protein alpha Subunits, Gs - metabolism
Histidine - genetics
Humans
Hydrolysis
Mutation - genetics
Phosphatidylinositols - metabolism
Pyrimidines - pharmacology
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - chemistry
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Signal Transduction - drug effects
Sulfonamides - pharmacology
Zinc - pharmacology
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Summary:In this study, we identified two previously described kinase inhibitors—3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(3-methyl-1H-pyrazol-5-yl)-8-(morpholinomethyl)imidazo[1,2-b]pyridazin-6-amine (LY2784544) and 1H-benzimidazole-4-carboxylic acid, 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-(4-morpholinyl)- (GSK2636771)—as novel GPR39 agonists by unbiased small-molecule-based screening using a β-arrestin recruitment screening approach (PRESTO-Tango). We characterized the signaling of LY2784544 and GSK2636771 and compared their signaling patterns with a previously described “GPR39-selective” agonist N-[3-chloro-4-[[[2-(methylamino)-6-(2-pyridinyl)-4- pyrimidinyl]amino]methyl]phenyl]methanesulfonamide (GPR39-C3) at both canonical and noncanonical signaling pathways. Unexpectedly, all three compounds displayed probe-dependent and pathway-dependent allosteric modulation by concentrations of zinc reported to be physiologic. LY2784544 and GS2636771 at GPR39 in the presence of zinc were generally as potent or more potent than their reported activities against kinases in whole-cell assays. These findings reveal an unexpected role of zinc as an allosteric potentiator of small-molecule-induced activation of GPR39 and expand the list of potential kinase off-targets to include understudied G protein–coupled receptors.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.116.106112