PT  - JOURNAL ARTICLE
AU  - Seiji Sato
AU  - Xi-Ping Huang
AU  - Wesley K. Kroeze
AU  - Bryan L. Roth
TI  - Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc
AID  - 10.1124/mol.116.106112
DP  - 2016 Dec 01
TA  - Molecular Pharmacology
PG  - 726--737
VI  - 90
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/90/6/726.short
4100  - http://molpharm.aspetjournals.org/content/90/6/726.full
SO  - Mol Pharmacol2016 Dec 01; 90
AB  - 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.