Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTWDC17)

• DTT Name: Growth hormone secretagogue receptor 1 (GHSR)
• Synonyms: Growth hormone secretagogue receptor; Ghrelin receptor; GHSR; GHS-R; GHRP; GH-releasing peptide receptor
• Gene Name: GHSR
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: GHSR_HUMAN
• TTD ID: T59604
• Sequence:
  MWNATPSEEPGFNLTLADLDWDASPGNDSLGDELLQLFPAPLLAGVTATCVALFVVGIAG
  NLLTMLVVSRFRELRTTTNLYLSSMAFSDLLIFLCMPLDLVRLWQYRPWNFGDLLCKLFQ
  FVSESCTYATVLTITALSVERYFAICFPLRAKVVVTKGRVKLVIFVIWAVAFCSAGPIFV
  LVGVEHENGTDPWDTNECRPTEFAVRSGLLTVMVWVSSIFFFLPVFCLTVLYSLIGRKLW
  RRRRGDAVVGASLRDQNHKQTVKMLAVVVFAFILCWLPFHVGRYLFSKSFEPGSLEIAQI
  SQYCNLVSFVLFYLSAAINPILYNIMSKKYRVAVFRLLGFEPFSQRKLSTLKDESSRAWT
  ESSINT
• Function: Receptor for ghrelin, coupled to G-alpha-11 proteins. Stimulates growth hormone secretion. Binds also other growth hormone releasing peptides (GHRP) (e.g. Met-enkephalin and GHRP-6) as well as non-peptide, low molecular weight secretagogues (e.g. L-692,429, MK-0677, adenosine).
• KEGG Pathway:
  cAMP signaling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GHRP-2	DMKGH0R	Growth hormone deficiency	5A61.3	Approved	[2]
Ibutamoren	DMFJ8LT	Fibromyalgia	MG30.01	Approved	[3]
Macimorelin	DMQYJIR	Growth hormone deficiency	5A61.3	Approved	[1]

9 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Anamorelin	DM6HXTS	Carbohydrate metabolism disorder	5C51.Z	Phase 3	[4]
TZP-101	DMOE582	Gastrointestinal disease	DE2Z	Phase 2b	[5]
GTP-200	DM03NQS	Solid tumour/cancer	2A00-2F9Z	Phase 2	[6]
Ibutamoren mesylate	DMN2CM0	Growth hormone deficiency	5A61.3	Phase 2	[7]
RQ-00000005	DMBHN4K	Frailty	MG2A	Phase 2	[8]
Tabimorelin	DMNL9HO	Growth hormone deficiency	5A61.3	Phase 2	[9]
Ipamorelin	DM9PJZT	Postoperative ileus	DA91-DB30	Phase 1/2	[10]
PF-05190457	DM7B2JC	Type-2 diabetes	5A11	Phase 1	[11]
ST-1141	DMX6V1L	Functional bowel disorder	DD91	Phase 1	[12]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CYT-009-GhrQb	DMCWRYS	Obesity	5B81	Discontinued in Phase 1/2	[13]
LY-444711	DMNPJL3	Growth hormone deficiency	5A61.3	Discontinued in Phase 1	[14]
SUN-11031	DMC1A42	Anorexia nervosa cachexia	6B80	Terminated	[17]

3 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AEZS-123	DMYIK5D	Alcohol dependence	6C40.2	Preclinical	[15]
EP-01492	DM2K51E	Obesity	5B81	Preclinical	[13]
TZP-301	DME8AL0	Metabolic disorder	5C50-5D2Z	Preclinical	[16]

21 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
4-(3-hexylureido)-N-phenylbenzenesulfonamide	DMC5GAW	Discovery agent	N.A.	Investigative	[18]
Abbott 14c	DMDBWT6	Discovery agent	N.A.	Investigative	[19]
AwFwLL-NH2	DMIWMJP	Discovery agent	N.A.	Investigative	[20]
DprwFwLL-NH2	DM35CKE	Discovery agent	N.A.	Investigative	[20]
DwFwLL-NH2	DMEUVIP	Discovery agent	N.A.	Investigative	[20]
EX-1311	DMBKM30	Metabolic disorder	5C50-5D2Z	Investigative	[21]
EX-1314	DMWF8U5	Cachexia	MG20	Investigative	[21]
GSK-894281	DMSOWPE	Gastric motility disorder	DA21	Investigative	[21]
GSK1614343	DMG6TL7	Discovery agent	N.A.	Investigative	[22]
HwFwLL-NH2	DM1D5F0	Discovery agent	N.A.	Investigative	[20]
JMV3008	DMB9U17	Discovery agent	N.A.	Investigative	[23]
KwFwLL-NH2	DM7RFUC	Discovery agent	N.A.	Investigative	[20]
NOX-B11	DMFW8O5	Obesity	5B81	Investigative	[21]
QwFwLL-NH2	DMQ7PIL	Discovery agent	N.A.	Investigative	[20]
RPKPfQwFwLL-NH2	DMAROTU	Discovery agent	N.A.	Investigative	[20]
RwFwLL-NH2	DMAU6FN	Discovery agent	N.A.	Investigative	[20]
SM-130,686	DMKZVEQ	Discovery agent	N.A.	Investigative	[24]
WFwGG-NH2	DMQS7BT	Discovery agent	N.A.	Investigative	[20]
WFwLL-NH2	DMOBXVL	Discovery agent	N.A.	Investigative	[20]
YIL781	DML1JY4	Discovery agent	N.A.	Investigative	[25]
[35S]ibutamoren	DMQ0NK8	Discovery agent	N.A.	Investigative	[26]

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	4.56E-01	-0.14	-0.74

References

• [1] National Cancer Institute Drug Dictionary (drug id 735530).
• [2] GH-releasing peptide-2 increases fat mass in mice lacking NPY: indication for a crucial mediating role of hypothalamic agouti-related protein. Endocrinology. 2002 Feb;143(2):558-68.
• [3] Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci U S A. 1995 Jul 18;92(15):7001-5.
• [4] Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers. Growth Horm IGF Res. 2009 Jun;19(3):267-73.
• [5] Contribution of protein binding to the pharmacokinetics of the ghrelin receptor agonist TZP-101 in healthy volunteers and adults with symptomatic gastroparesis: two randomized, double-blind studies and a binding profile study. Clin Drug Investig. 2009;29(6):409-18.
• [6] Orphan GPCR research. Br J Pharmacol. 2008 March; 153(Suppl 1): S339-S346.
• [7] Effects of oral administration of ibutamoren mesylate, a nonpeptide growth hormone secretagogue, on the growth hormone-insulin-like growth factor I axis in growth hormone-deficient children. Clin Pharmacol Ther. 2001 Jul;70(1):91-8.
• [8] Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor. Br J Pharmacol. 2014 Mar;171(5):1275-86.
• [9] Pharmacological characterisation of a new oral GH secretagogue, NN703. Eur J Endocrinol. 1999 Aug;141(2):180-9.
• [10] Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus.J Pharmacol Exp Ther.2009 Jun;329(3):1110-6.
• [11] A gift for research. SciBX 7(6); doi:10.1038/scibx.2014.160. Feb. 13 2014
• [12] The Prokinetic Face of Ghrelin. International Journal of Peptides Volume 2010 (2010), Article ID 493614, Page(11).
• [13] Emerging drugs for obesity: linking novel biological mechanisms to pharmaceutical pipelines. Expert Opin Emerg Drugs. 2005 Aug;10(3):643-60.
• [14] Synthesis and biological evaluation of an orally active ghrelin agonist that stimulates food consumption and adiposity in rats. Bioorg Med Chem Lett. 2004 Dec 6;14(23):5873-6.
• [15] 2011 Pipeline of Aeterna Zentaris.
• [16] Clinical pipeline report, company report or official report of Tranzyme Pharma (2011).
• [17] Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs. 2006 May;11(2):315-36.
• [18] Discovery and optimization of novel 4-[(aminocarbonyl)amino]-N-[4-(2-aminoethyl)phenyl]benzenesulfonamide ghrelin receptor antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6237-40.
• [19] Discovery and pharmacological evaluation of growth hormone secretagogue receptor antagonists. J Med Chem. 2006 Jul 27;49(15):4459-69.
• [20] Identification of an efficacy switch region in the ghrelin receptor responsible for interchange between agonism and inverse agonism. J Biol Chem. 2007 May 25;282(21):15799-811.
• [21] 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: 246).
• [22] Discovery process and characterization of novel carbohydrazide derivatives as potent and selective GHSR1a antagonists. ChemMedChem. 2010 Sep 3;5(9):1450-5.
• [23] Toward potent ghrelin receptor ligands based on trisubstituted 1,2,4-triazole structure. 2. Synthesis and pharmacological in vitro and in vivo eval... J Med Chem. 2007 Nov 15;50(23):5790-806.
• [24] Oxindole derivatives as orally active potent growth hormone secretagogues. J Med Chem. 2001 Dec 20;44(26):4641-9.
• [25] Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology. 2007 Nov;148(11):5175-85.
• [26] Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol. 1997 Apr;11(4):415-23.