Target Information

Target General Infomation
Target ID
T25608
Former ID
TTDNC00653
Target Name
GPR40
Gene Name
FFAR1
Synonyms
Free fatty acid receptor 1; Gprotein coupled receptor 40; FFAR1
Target Type
Clinical Trial
Disease Diabetes [ICD9: 253.5, 588.1; ICD10: E23.2, N25.1]
Non-insulin dependent diabetes [ICD10: E11.9]
Type 2 diabetes [ICD9: 250; ICD10: E11]
Function
G-protein coupled receptor for medium and long chain saturated and unsaturated fatty acids that plays an important role in glucose homeostasis. Fatty acid binding increases glucose- stimulated insulin secretion, and may also enhance the secretion of glucagon-like peptide 1 (GLP-1). May also play a role in bone homeostasis; receptor signaling activates pathways that inhibit osteoclast differentiation (By similarity). Ligand binding leads to a conformation change that triggers signaling via G-proteins that activate phospholipase C, leading to an increase of the intracellular calcium concentration. Seems to act through a G(q) and G(i)-mediated pathway.
BioChemical Class
GPCR rhodopsin
UniProt ID
O14842
Sequence
MDLPPQLSFGLYVAAFALGFPLNVLAIRGATAHARLRLTPSLVYALNLGCSDLLLTVSLP
LKAVEALASGAWPLPASLCPVFAVAHFFPLYAGGGFLAALSAGRYLGAAFPLGYQAFRRP
CYSWGVCAAIWALVLCHLGLVFGLEAPGGWLDHSNTSLGINTPVNGSPVCLEAWDPASAG
PARFSLSLLLFFLPLAITAFCYVGCLRALARSGLTHRRKLRAAWVAGGALLTLLLCVGPY
NASNVASFLYPNLGGSWRKLGLITGAWSVVLNPLVTGYLGRGPGLKTVCAARTQGGKSQK
Drugs and Mode of Action
Drug(s) Fasiglifam hemihydrate Drug Info Phase 3 Type 2 diabetes [524575]
TAK-875 Drug Info Phase 3 Type 2 diabetes [523927], [541618]
JTT-851 Drug Info Phase 2 Type 2 diabetes [524085]
P-1736 Drug Info Phase 2 Diabetes [532535]
LY-2881835 Drug Info Phase 1 Type 2 diabetes [523492]
P11187 Drug Info Phase 1 Type 2 diabetes [524321]
Agonist alpha-linolenic acid Drug Info [526570]
AMG-837 Drug Info [531990]
CNX-011 Drug Info [543582]
compound B Drug Info [529472]
GW9508 Drug Info [528205]
JTT-851 Drug Info [544438]
medica 16 Drug Info [526529]
TUG-424 Drug Info [529762]
TUG-469 Drug Info [543582]
TUG-770 Drug Info [532363]
Modulator Fasiglifam hemihydrate Drug Info [532423], [532513]
LY-2881835 Drug Info [544438]
P-1736 Drug Info [532535]
P11187 Drug Info [544438]
TAK-875 Drug Info [533183]
Antagonist GW1100 Drug Info [528205]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway Insulin secretion
Reactome G alpha (q) signalling events
Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion
WikiPathways GPCRs, Class A Rhodopsin-like
Incretin Synthesis, Secretion, and Inactivation
Gastrin-CREB signalling pathway via PKC and MAPK
Integration of energy metabolism
GPCR ligand binding
GPCR downstream signaling
References
Ref 523492ClinicalTrials.gov (NCT01358981) A Study of LY2881835 in Healthy People and People With Diabetes. U.S. National Institutes of Health.
Ref 523927ClinicalTrials.gov (NCT01609582) Study of TAK-875 in Adults With Type 2 Diabetes and Cardiovascular Disease or Risk Factors for Cardiovascular Disease. U.S. National Institutes of Health.
Ref 524085ClinicalTrials.gov (NCT01699737) Safety and Efficacy Study of JTT-851 in Patients With Type 2 Diabetes Mellitus. U.S. National Institutes of Health.
Ref 524321ClinicalTrials.gov (NCT01874366) Determination of Safety,Tolerability,Pharmacokinetics,Food Effect& Pharmacodynamics of Single & Multiple Doses of P11187. U.S. National Institutes of Health.
Ref 524575ClinicalTrials.gov (NCT02015780) Fasiglifam in Type 2 Diabetic Subjects With Chronic Kidney Disease Stage 4 or 5 on Hemodialysis. U.S. National Institutes of Health.
Ref 532535Discovery of p1736, a novel antidiabetic compound that improves peripheral insulin sensitivity in mice models. PLoS One. 2013 Oct 23;8(10):e77946.
Ref 541618(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6484).
Ref 526529A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun. 2003 Feb 7;301(2):406-10.
Ref 526570Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature. 2003 Mar 13;422(6928):173-6. Epub 2003 Feb 23.
Ref 528205Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules. Br J Pharmacol. 2006 Jul;148(5):619-28. Epub 2006 May 15.
Ref 529472Selective small-molecule agonists of G protein-coupled receptor 40 promote glucose-dependent insulin secretion and reduce blood glucose in mice. Diabetes. 2008 Aug;57(8):2211-9.
Ref 529762Discovery of potent and selective agonists for the free fatty acid receptor 1 (FFA(1)/GPR40), a potential target for the treatment of type II diabetes. J Med Chem. 2008 Nov 27;51(22):7061-4.
Ref 531990Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor. Mol Pharmacol. 2012 Nov;82(5):843-59.
Ref 532363Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes. ACS Med Chem Lett. 2013 May 9;4(5):441-445. Epub 2013 Apr 8.
Ref 532423TAK-875, a GPR40/FFAR1 agonist, in combination with metformin prevents progression of diabetes and beta-cell dysfunction in Zucker diabetic fatty rats. Br J Pharmacol. 2013 Oct;170(3):568-80.
Ref 532513A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric modulator of FFAR1. PLoS One. 2013 Oct 10;8(10):e76280.
Ref 532535Discovery of p1736, a novel antidiabetic compound that improves peripheral insulin sensitivity in mice models. PLoS One. 2013 Oct 23;8(10):e77946.
Ref 533183Efficacy and safety of fasiglifam (TAK-875), a G protein-coupled receptor 40 agonist, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise: a randomized, double-blind, placebo-controlled, phase III trial. Diabetes Obes Metab. 2015 Jul;17(7):675-81.
Ref 543582(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 225).
Ref 544438Treatment of Type 2 Diabetes by Free Fatty Acid Receptor Agonists. Front Endocrinol (Lausanne) 2014; 5: 137.

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