Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists

Peukert, Stefan; Hughes, Richard L.; Nunez, Jill; He, Guo Wei; Zhao, Yan; Jain, Rishi K.; Llamas, Luis; Luchansky, Sarah J.; Carlson, Adam; Liang, Guiqing; Kunjathoor, Vidya V.; Pietropaolo, M; Shapiro, Jeffrey; Castellana, Anja; Wu, Xiaoping; Bose, Avirup

doi:10.1021/ml500240d

Cited by 38 publications

(52 citation statements)

References 20 publications

(31 reference statements)

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“…5). This is in agreement with a previous study (Peukert et al, 2014), which showed an EC 50 value of 60 nM and an efficacy of 64% of the activity shown by 25 mM forskolin. Another study found that the GPR39 agonists AZ1395, 3,4-bis-(2-imidazol-1-ylethoxy)-benzonitrile; AZ4237, 6-[(4-chlorophenyl)methyl]-7-hydroxy-5-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid; AZ7914, 6-(3-chloro-2-fluoro-benzoyl)-2-(2-methylthiazol-4-yl) -3,5,7,8-tetrahydropyrido-[4,3-d]pyrimidin-4-one also stimulated cAMP responses without Zn 21 (Fjellström et al, 2015); however, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) was used in that study, which makes estimation of the "true" pharmacological parameters of these compounds difficult.…”

Section: Discussionsupporting

confidence: 94%

“…The structures of these compounds are similar to each other, but are markedly different from the GPR39-C3 compound that has previously been reported to be an agonist at GPR39 ( Fig. 1B; Peukert et al, 2014). When tested at 11 other GPCRs, neither of these compounds showed agonist activity (Fig.…”

Section: Resultsmentioning

confidence: 43%

“…of at least three independent experiments performed in quadruplicate (compounds and ZnCl 2 ) or duplicate (NiCl 2 ). agonist GPR39-C3 (Peukert et al, 2014), as well as the two compounds discovered in our screens, LY2784544 and GSK2636771 (Fig. 1), at various concentrations of Zn 21 in the TANGO assay (Fig.…”

Section: Resultsmentioning

confidence: 75%

“…Zn 21 stimulates signaling via the Gq and b-arrestin pathways, as well as the Gs pathway (Holst et al, 2007). Recently, three groups reported small-molecule agonists for GPR39 (Boehm et al, 2013;Peukert et al, 2014;Fjellström et al, 2015). However, the signaling pathways induced by these agonists, and their relationship to Zn 21 concentrations, remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

et al. 2016

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In this study, we identified two previously described kinase inhibitors-3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(3-methyl-1H-pyrazol-agonists by unbiased small-molecule-based screening using a b-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"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.

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Section: Discussionsupporting

confidence: 94%

Section: Resultsmentioning

confidence: 43%

Section: Resultsmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

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Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

et al. 2016

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“…GPR39 is a conserved orphan GPCR that has been shown to be involved in zinc ion transport as well as other aspects of metabolic regulation [8]. Recently, a new compound named TC-G 1008 (also named as GPR39-C3) was developed based on 2-pyridylpyrimidines and has been shown to be highly specific in binding to GPR39, making it a powerful tool to investigate the function of this receptor in diverse cell types [9,10]. GPR39 has been shown to be expressed in different osteoblast cell lines [11].…”

Section: Gpr39 Agonist Tc-g 1008 Promotes Osteoblast Differentiationmentioning

confidence: 99%

GPR39 agonist TC-G 1008 promotes osteoblast differentiation and mineralization in MC3T3-E1 cells

Chai

Zhang

Chang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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Osteoporosis-related bone fracture and falls have a severe impact on patients' daily lives. Osteoblasts are bone-building cells that play a vital role in bone formation and remodeling. Imbalanced osteoblast differentiation could lead to osteoporosis. GPR39 is an orphan G protein-coupled receptor that mediates metabolic pathways. In this study, we show that GPR39 is expressed in MC3T3-E1 cells. Osteoblast differentiation culture media induces GPR39, suggesting that GPR39 is a differentiation-responsive factor. Activation of GPR39 using its selective agonist TC-G 1008 induces alkaline phosphatase (ALP), osteocalcin (OCN), and type I collagen (Col-I) expression, and increases cellular ALP activity and calcium deposition, implying that GPR activation promotes cells toward osteoblast differentiation. Treatment with TC-G 1008 also increases Runx-2 expression and AMPK activation. However, the inhibition of AMPK by Compound C abolished TC-G 1008-mediated ALP, OCN, and Col-I induction, and reduces ALP activity and cellular calcium deposition as well as Runx-2 induction. These data indicate that TC-G 1008-mediated GPR39 activation involves AMPK-mediated Runx-2 induction. In summary, our study uncovers a new role of GPR39 activation in osteoblast differentiation, implying that GPR39 could be a promising therapeutic target for osteoporosis. ARTICLE HISTORY

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Pharmacology and physiology of gastrointestinal enteroendocrine cells

Mace

Tehan

Marshall

2015

Pharmacology Res & Perspec

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Gastrointestinal (GI) polypeptides are secreted from enteroendocrine cells (EECs). Recent technical advances and the identification of endogenous and synthetic ligands have enabled exploration of the pharmacology and physiology of EECs. Enteroendocrine signaling pathways stimulating hormone secretion involve multiple nutrient transporters and G protein-coupled receptors (GPCRs), which are activated simultaneously under prevailing nutrient conditions in the intestine following a meal. The majority of studies investigate hormone secretion from EECs in response to single ligands and although the mechanisms behind how individual signaling pathways generate a hormonal output have been well characterized, our understanding of how these signaling pathways converge to generate a single hormone secretory response is still in its infancy. However, a picture is beginning to emerge of how nutrients and full, partial, or allosteric GPCR ligands differentially regulate the enteroendocrine system and its interaction with the enteric and central nervous system. So far, activation of multiple pathways underlies drug discovery efforts to harness the therapeutic potential of the enteroendocrine system to mimic the phenotypic changes observed in patients who have undergone Roux-en-Y gastric surgery. Typically obese patients exhibit ∼30% weight loss and greater than 80% of obese diabetics show remission of diabetes. Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy. Furthermore, allosteric modulators with their increased selectivity, self-limiting activity, and structural novelty may translate into more promising enteroendocrine drugs. Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available. Here, we review the pharmacology and physiology of the EEC system.

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Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists

Cited by 38 publications

References 20 publications

Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

GPR39 agonist TC-G 1008 promotes osteoblast differentiation and mineralization in MC3T3-E1 cells

Pharmacology and physiology of gastrointestinal enteroendocrine cells

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