دورية أكاديمية
GPR40-Mediated G α 12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets.
| العنوان: | GPR40-Mediated G α 12 Activation by Allosteric Full Agonists Highly Efficacious at Potentiating Glucose-Stimulated Insulin Secretion in Human Islets. |
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| المؤلفون: | Rives ML; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.) mrives1@its.jnj.com., Rady B; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)., Swanson N; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)., Zhao S; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)., Qi J; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)., Arnoult E; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)., Bakaj I; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)., Mancini A; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)., Breton B; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)., Lee SP; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)., Player MR; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.)., Pocai A; Molecular and Cellular Pharmacology, Janssen Research & Development, LLC, La Jolla, California (M.-L.R., N.S.); Cardiovascular and Metabolism (B.R., S.Z., J.Q., I.B., S.P.L., M.R.P., A.P.), and Computational Chemistry (E.A.), Janssen Research & Development, LLC, Spring House, Pennsylvania; and Domain Therapeutics NA Inc., Montreal, Quebec, Canada (A.M., B.B.). |
| المصدر: | Molecular pharmacology [Mol Pharmacol] 2018 Jun; Vol. 93 (6), pp. 581-591. Date of Electronic Publication: 2018 Mar 23. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics |
| مواضيع طبية MeSH: | GTP-Binding Protein alpha Subunits, G12-G13/*metabolism , Glucose/*metabolism , Insulin/*metabolism , Insulin Secretion/*physiology , Islets of Langerhans/*metabolism , Receptors, G-Protein-Coupled/*metabolism, Animals ; Benzofurans/pharmacology ; CHO Cells ; Cell Line ; Cricetulus ; HEK293 Cells ; Humans ; Hypoglycemic Agents/pharmacology ; Insulin Secretion/drug effects ; Islets of Langerhans/drug effects ; Protein Kinase C/metabolism ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Sulfones/pharmacology |
| مستخلص: | GPR40 is a clinically validated molecular target for the treatment of diabetes. Many GPR40 agonists have been identified to date, with the partial agonist fasiglifam (TAK-875) reaching phase III clinical trials before its development was terminated due to off-target liver toxicity. Since then, attention has shifted toward the development of full agonists that exhibit superior efficacy in preclinical models. Full agonists bind to a distinct binding site, suggesting conformational plasticity and a potential for biased agonism. Indeed, it has been suggested that alternative pharmacology may be required for meaningful efficacy. In this study, we described the discovery and characterization of Compound A, a newly identified GPR40 allosteric full agonist highly efficacious in human islets at potentiating glucose-stimulated insulin secretion. We compared Compound A-induced GPR40 activity to that induced by both fasiglifam and AM-1638, another allosteric full agonist previously reported to be highly efficacious in preclinical models, at a panel of G proteins. Compound A was a full agonist at both the G α q and G α i2 pathways, and in contrast to fasiglifam Compound A also induced G α 12 coupling. Compound A and AM-1638 displayed similar activity at all pathways tested. The G α Competing Interests: The authors declare no conflict of interest. (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.) |
| المشرفين على المادة: | 0 (Benzofurans) 0 (Hypoglycemic Agents) 0 (Insulin) 0 (Receptors, G-Protein-Coupled) 0 (Sulfones) 0 (TAK-875) EC 2.7.10.- (protein kinase D) EC 2.7.11.13 (Protein Kinase C) EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, G12-G13) IY9XDZ35W2 (Glucose) |
| تواريخ الأحداث: | Date Created: 20180325 Date Completed: 20190201 Latest Revision: 20190201 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1124/mol.117.111369 |
| PMID: | 29572336 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0111 |
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| DOI: | 10.1124/mol.117.111369 |