Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTB8FUC)

• DTT Name: Free fatty acid receptor 1 (GPR40)
• Synonyms: Gprotein coupled receptor 40; FFAR1
• Gene Name: FFAR1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: FFAR1_HUMAN
• TTD ID: T25608
• Sequence:
  MDLPPQLSFGLYVAAFALGFPLNVLAIRGATAHARLRLTPSLVYALNLGCSDLLLTVSLP
  LKAVEALASGAWPLPASLCPVFAVAHFFPLYAGGGFLAALSAGRYLGAAFPLGYQAFRRP
  CYSWGVCAAIWALVLCHLGLVFGLEAPGGWLDHSNTSLGINTPVNGSPVCLEAWDPASAG
  PARFSLSLLLFFLPLAITAFCYVGCLRALARSGLTHRRKLRAAWVAGGALLTLLLCVGPY
  NASNVASFLYPNLGGSWRKLGLITGAWSVVLNPLVTGYLGRGPGLKTVCAARTQGGKSQK
• 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. 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.
• KEGG Pathway: Insulin secretion (hsa04911)
• Reactome Pathway:
  Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion (R-HSA-434316)
  G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DTT

10 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fasiglifam hemihydrate	DMTGYSO	Type-2 diabetes	5A11	Phase 3	[1]
TAK-875	DMIM5AP	Type-2 diabetes	5A11	Phase 3	[2]
JTT-851	DMED5J6	Type-2 diabetes	5A11	Phase 2	[3]
P-1736	DMEYQPN	Diabetic complication	5A2Y	Phase 2	[4]
PBI-4050	DMPXK27	Idiopathic pulmonary fibrosis	CB03.4	Phase 2	[5]
CPL207-280CA	DMFMGZR	Type 2 diabetes	5A11	Phase 1	[6]
LY-2881835	DM5EXJV	Type-2 diabetes	5A11	Phase 1	[3]
LY2922470	DMGLTE2	Type 2 diabetes	5A11	Phase 1	[7]
P11187	DMXZOI0	Type-2 diabetes	5A11	Phase 1	[3]
SHR0534	DMGFTAI	Type 2 diabetes	5A11	Phase 1	[6]

3 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BMS-986118	DM4BZEJ	Type 2 diabetes	5A11	Preclinical	[8]
CNX-011-67	DM1H8D6	Type 2 diabetes	5A11	Preclinical	[9]
DS-1558	DMMI2EY	Type 2 diabetes	5A11	Preclinical	[10]

10 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
alpha-linolenic acid	DMY64HE	Discovery agent	N.A.	Investigative	[11]
AMG-837	DMNHM1B	Discovery agent	N.A.	Investigative	[12]
CNX-011	DM5T401	Non-insulin dependent diabetes	5A11	Investigative	[13]
GW1100	DM3DXM0	Discovery agent	N.A.	Investigative	[14]
GW9508	DMVKZ5I	Discovery agent	N.A.	Investigative	[14]
medica 16	DML2GFB	Discovery agent	N.A.	Investigative	[15]
PMID18477808CB	DM0G42B	Discovery agent	N.A.	Investigative	[16]
TUG-424	DM2H0PQ	Discovery agent	N.A.	Investigative	[17]
TUG-469	DM8YN42	Non-insulin dependent diabetes	5A11	Investigative	[13]
TUG-770	DM487HF	Discovery agent	N.A.	Investigative	[18]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Type 2 diabetes	5A11	Liver tissue	6.14E-01	-0.08	-1.33

References

• [1] A novel antidiabetic drug, fasiglifam/TAK-875, acts as an ago-allosteric modulator of FFAR1. PLoS One. 2013 Oct 10;8(10):e76280.
• [2] Efficacy 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.
• [3] Treatment of Type 2 Diabetes by Free Fatty Acid Receptor Agonists. Front Endocrinol (Lausanne) 2014; 5: 137.
• [4] Discovery of p1736, a novel antidiabetic compound that improves peripheral insulin sensitivity in mice models. PLoS One. 2013 Oct 23;8(10):e77946.
• [5] Phase 2 clinical trial of PBI-4050 in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2019 Mar 18;53(3):1800663.
• [6] Targeting metabolic dysregulation for fibrosis therapy. Nat Rev Drug Discov. 2020 Jan;19(1):57-75.
• [7] The Discovery, Preclinical, and Early Clinical Development of Potent and Selective GPR40 Agonists for the Treatment of Type 2 Diabetes Mellitus (LY2881835, LY2922083, and LY2922470). J Med Chem. 2016 Dec 22;59(24):10891-10916.
• [8] Discovery of Potent and Orally Bioavailable Dihydropyrazole GPR40 Agonists. J Med Chem. 2018 Feb 8;61(3):681-694.
• [9] CNX-011-67, a novel GPR40 agonist, enhances glucose responsiveness, insulin secretion and islet insulin content in n-STZ rats and in islets from type 2 diabetic patients. BMC Pharmacol Toxicol. 2014 Mar 25;15:19.
• [10] Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist. ACS Med Chem Lett. 2015 Jan 13;6(3):266-70.
• [11] Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature. 2003 Mar 13;422(6928):173-6.
• [12] Identification and pharmacological characterization of multiple allosteric binding sites on the free fatty acid 1 receptor. Mol Pharmacol. 2012 Nov;82(5):843-59.
• [13] URL: 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).
• [14] Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small... Br J Pharmacol. 2006 Jul;148(5):619-28.
• [15] A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun. 2003 Feb 7;301(2):406-10.
• [16] Selective 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.
• [17] Discovery 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.
• [18] Discovery 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.