Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT9O6WS)

• DTT Name: Glucagon receptor (GCGR)
• Synonyms: GLR; GL-R
• Gene Name: GCGR
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR secretin
• UniProt ID: GLR_HUMAN
• TTD ID: T60182
• Sequence:
  MPPCQPQRPLLLLLLLLACQPQVPSAQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNR
  TFDKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQ
  CQMDGEEIEVQKEVAKMYSSFQVMYTVGYSLSLGALLLALAILGGLSKLHCTRNAIHANL
  FASFVLKASSVLVIDGLLRTRYSQKIGDDLSVSTWLSDGAVAGCRVAAVFMQYGIVANYC
  WLLVEGLYLHNLLGLATLPERSFFSLYLGIGWGAPMLFVVPWAVVKCLFENVQCWTSNDN
  MGFWWILRFPVFLAILINFFIFVRIVQLLVAKLRARQMHHTDYKFRLAKSTLTLIPLLGV
  HEVVFAFVTDEHAQGTLRSAKLFFDLFLSSFQGLLVAVLYCFLNKEVQSELRRRWHRWRL
  GKVLWEERNTSNHRASSSPGHGPPSKELQFGRGGGSQDSSAETPLAGGLPRLAESPF
• Function: Regulates the rate of hepatic glucose production by promoting glycogen hydrolysis and gluconeogenesis. Plays an important role in mediating the responses to fasting. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Promotes activation of adenylate cyclase. Besides, plays a role in signaling via a phosphatidylinositol-calcium second messenger system. G-protein coupled receptor for glucagon that plays a central role in the regulation of blood glucose levels and glucose homeostasis.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Glucagon signaling pathway (hsa04922)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (s) signalling events (R-HSA-418555)
  Glucagon-type ligand receptors (R-HSA-420092)
  Glucagon signaling in metabolic regulation (R-HSA-163359)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dasiglucagon	DM74SVE	Hypoglycemia	5A41	Approved	[2]
Glucagon recombinant	DMFLUTR	Hypoglycemia	5A41	Approved	[1]

16 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Retatrutide	DM8WU0Q	Obesity	5B81	Phase 3	[3]
Efinopegdutide	DMAN2V2	Non-alcoholic steatohepatitis	DB92.1	Phase 2	[4]
LGD-6972	DMPL9KG	Type-2 diabetes	5A11	Phase 2	[5]
LY-2409021	DMZOIP4	Type-2 diabetes	5A11	Phase 2	[6]
LY2944876	DML6XWR	Diabetic complication	5A2Y	Phase 2	[7]
LY3437943	DMN37M6	Obesity	5B81	Phase 2	[8]
MK-8521	DMVNAYE	Type-2 diabetes	5A11	Phase 2	[9]
PF-06291874	DMN94QM	Type-2 diabetes	5A11	Phase 2	[10]
REMD 477	DM13OVF	Type-1 diabetes	5A10	Phase 2	[11]
TT-401	DMRQ0SA	Type-2 diabetes	5A11	Phase 2	[9]
DD01	DM0JKZ6	Obesity	5B81	Phase 1	[12]
LY3305677	DMJMLLW	Type 2 diabetes	5A11	Phase 1	[13]
Pemvidutide	DMVOG8A	Obesity	5B81	Phase 1	[14]
REGN1193	DMYBELW	Type-2 diabetes	5A11	Phase 1	[15]
SAR425899	DM53IPE	Diabetic complication	5A2Y	Phase 1	[16]
ZP2929	DMRVDUM	Type-1 diabetes	5A10	Phase 1	[17]

33 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3-substituted-2-furancarboxylic acid hydrazide derivative 1	DMKEOH8	N. A.	N. A.	Patented	[18]
3-substituted-2-furancarboxylic acid hydrazide derivative 5	DMLK29E	N. A.	N. A.	Patented	[18]
Aromatic ring compound 1	DMJX6DV	N. A.	N. A.	Patented	[18]
Aromatic ring compound 2	DMMAS3G	N. A.	N. A.	Patented	[18]
Aromatic ring compound 3	DM43APD	N. A.	N. A.	Patented	[18]
Aromatic ring compound 4	DMXGLST	N. A.	N. A.	Patented	[18]
Biphenyl carboxamidopropanoic acid derivative 1	DM6803W	N. A.	N. A.	Patented	[18]
Biphenyl carboxamidopropanoic acid derivative 2	DMQF2XN	N. A.	N. A.	Patented	[18]
Biphenyl carboxamidopropanoic acid derivative 3	DMLOVMP	N. A.	N. A.	Patented	[18]
Biphenyl carboxamidopropanoic acid derivative 4	DM715E8	N. A.	N. A.	Patented	[18]
Heterocycle-containing compound 1	DM8PHBG	N. A.	N. A.	Patented	[18]
Heterocycle-containing compound 2	DM2KVMT	N. A.	N. A.	Patented	[18]
Heterocycle-containing compound 3	DMHMTF7	N. A.	N. A.	Patented	[18]
Heterocycle-containing compound 4	DM6IRJL	N. A.	N. A.	Patented	[18]
Heterocycle-containing compound 5	DM6EY5Z	N. A.	N. A.	Patented	[18]
Picolinamido propanoic acid derivative 1	DMUP4DX	N. A.	N. A.	Patented	[18]
Picolinamido propanoic acid derivative 2	DMR74ET	N. A.	N. A.	Patented	[18]
Picolinamido propanoic acid derivative 3	DMP1RV5	N. A.	N. A.	Patented	[18]
PMID25828189-Compound-19	DMEC1TR	N. A.	N. A.	Patented	[18]
PMID25828189-Compound-21	DM7D0CT	N. A.	N. A.	Patented	[18]
PMID25828189-Compound-22	DMC2O0Q	N. A.	N. A.	Patented	[18]
Pyrrolidine derivative 6	DMJ3ZP2	N. A.	N. A.	Patented	[18]
Pyrrolidine derivative 7	DMIOJD6	N. A.	N. A.	Patented	[18]
Pyrrolidine derivative 8	DMWPXJ5	N. A.	N. A.	Patented	[18]
Quinolinyl compound 1	DMENZPR	N. A.	N. A.	Patented	[18]
Quinolinyl compound 2	DMGLK92	N. A.	N. A.	Patented	[18]
Spiroimidazolone derivative 1	DMCPVRU	N. A.	N. A.	Patented	[18]
Spiroimidazolone derivative 2	DM3EAHB	N. A.	N. A.	Patented	[18]
Spiroimidazolone derivative 3	DM02J8N	N. A.	N. A.	Patented	[18]
Spiroimidazolone derivative 4	DMXIHPT	N. A.	N. A.	Patented	[18]
Spiroimidazolone derivative 5	DM5A62X	N. A.	N. A.	Patented	[18]
Spiroimidazolone derivative 6	DMJN5CI	N. A.	N. A.	Patented	[18]
Spiroimidazolone derivative 7	DM5A4TP	N. A.	N. A.	Patented	[18]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BAY-27-9955	DMGDSCK	Type-2 diabetes	5A11	Discontinued in Phase 1	[19]
BAY-73-7977	DMKJ3IA	Diabetic complication	5A2Y	Discontinued in Phase 1	[20]
NN-2501	DM95NDT	Type-2 diabetes	5A11	Discontinued in Phase 1	[21]
DIO-901	DMAK3V7	Type-1 diabetes	5A10	Terminated	[22]
NNC-252504	DM0BYU2	Type-2 diabetes	5A11	Terminated	[23]

13 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BI-32169	DMN052T	Discovery agent	N.A.	Investigative	[24]
Des-His1[Glu9]glucagon-NH2	DMGTAZ4	Discovery agent	N.A.	Investigative	[25]
DSR-17759	DM4EKHR	Non-insulin dependent diabetes	5A11	Investigative	[26]
DwLIP-GCGRrx	DMW9GT7	Diabetic complication	5A2Y	Investigative	[27]
glucagon-(1-6)	DMVWDHM	Discovery agent	N.A.	Investigative	[28]
hGCGR antagonist	DMOIPYD	Discovery agent	N.A.	Investigative	[29]
L-168049	DM3UGMD	Diabetic complication	5A2Y	Investigative	[26]
MAR-531	DMKT21X	Hypoglycemia	5A41	Investigative	[26]
NNC 92-1687	DMPQ1HL	Discovery agent	N.A.	Investigative	[30]
[des-His1,Tyr5,Glu9,D-Ala10]glucagon-NH2	DM1EPZB	Discovery agent	N.A.	Investigative	[31]
[des-His1,Tyr5,Glu9,D-Phe10]glucagon-NH2	DM06Q2V	Discovery agent	N.A.	Investigative	[31]
[des-His1,Tyr5,Glu9,D-Tyr10]glucagon-NH2	DMFLVED	Discovery agent	N.A.	Investigative	[31]
[des-His1,Tyr5,Glu9]glucagon-NH2	DM93I0B	Discovery agent	N.A.	Investigative	[31]

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	7.24E-02	-0.52	-0.92

References

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• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021
• [3] Is retatrutide (LY3437943), a GLP-1, GIP, and glucagon receptor agonist a step forward in the treatment of diabetes and obesity? Expert Opin Investig Drugs. 2023 May;32(5):355-359.
• [4] Emerging glucagon-like peptide 1 receptor agonists for the treatment of obesity. Expert Opin Emerg Drugs. 2021 Sep;26(3):231-243.
• [5] Addressing Unmet Medical Needs in Type 2 Diabetes: A Narrative Review of Drugs under Development. Curr Diabetes Rev. 2015 March; 11(1): 17-31.
• [6] Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes. Diabetes Obes Metab. 2015 Apr;17(4):414-22.
• [7] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [8] LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 2022 Sep 6;34(9):1234-1247.e9.
• [9] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [10] Clinical pipeline report, company report or official report of pfizer.
• [11] Effect of a glucagon receptor antibody (REMD-477) in type 1 diabetes: A randomized controlled trial. Diabetes Obes Metab. 2018 May;20(5):1302-1305.
• [12] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2023. Adis Insight
• [13] IBI362?(LY3305677), a weekly-dose GLP-1 and glucagon receptor dual agonist, in Chinese adults with overweight or obesity: A randomised, placebo-controlled, multiple ascending dose phase 1b study. EClinicalMedicine. 2021 Aug 13;39:101088.
• [14] Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis. Sci Rep. 2022 Apr 23;12(1):6666.
• [15] A first-in-human pharmacodynamic and pharmacokinetic study of a fully human anti-glucagon receptor monoclonal antibody in normal healthy volunteers. Diabetes Obes Metab. 2018 Feb;20(2):283-291.
• [16] Company report (Sanofi) (drug: LIXisenatide)
• [17] Company report (Zealandpharma)
• [18] Small molecule glucagon receptor antagonists: a patent review (2011 - 2014).Expert Opin Ther Pat. 2015 Jul;25(7):819-30.
• [19] Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia. 2001 Nov;44(11):2018-24.
• [20] WO patent application no. 2012,0351,39, Prodrugs comprising an exendin linker conjugate.
• [21] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018428)
• [22] Effects of low-dose and high-dose glucagon on glucose production and gluconeogenesis in humans. Metabolism. 2000 Jan;49(1):39-46.
• [23] A novel glucagon receptor antagonist, NNC 25-0926, blunts hepatic glucose production in the conscious dog. J Pharmacol Exp Ther. 2007 May;321(2):743-52.
• [24] BI-32169, a bicyclic 19-peptide with strong glucagon receptor antagonist activity from Streptomyces sp. J Nat Prod. 2004 Sep;67(9):1528-31.
• [25] Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor. Bioorg Med Chem Lett. 2005 Mar 1;15(5):1401-5.
• [26] 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: 251).
• [27] Clinical pipeline report, company report or official report of ISIS Pharmaceuticals (2009).
• [28] Glucagon1-6 binds to the glucagon receptor and activates hepatic adenylate cyclase. J Biol Chem. 1979 Jan 25;254(2):268-9.
• [29] A novel glucagon receptor antagonist inhibits glucagon-mediated biological effects. Diabetes. 2004 Dec;53(12):3267-73.
• [30] Discovery and structure-activity relationship of the first non-peptide competitive human glucagon receptor antagonists. J Med Chem. 1998 Dec 17;41(26):5150-7.
• [31] Topographical amino acid substitution in position 10 of glucagon leads to antagonists/partial agonists with greater binding differences. J Med Chem. 1996 Jun 21;39(13):2449-55.