Target Information

Target General Information

Target ID

T12475 (Former ID: TTDS00273)

Target Name

Gonadotropin-releasing hormone receptor (GNRHR)

Synonyms

Hypothalamic gonadotropin-releasing hormone receptor; Gonadotrophin releasing hormone receptor; GnRH-R; GnRH receptor; GRHR

Gene Name

GNRHR

Target Type

Successful target

[1]

Disease

[+] 6 Target-related Diseases

Endometriosis [ICD-11: GA10]

Ovarian developmental anomaly [ICD-11: LB45]

Ovarian dysfunction [ICD-11: 5A80]

Pituitary gland disorder [ICD-11: 5A60-5A61]

Prostate cancer [ICD-11: 2C82]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Function

Receptor for gonadotropin releasing hormone (GnRH) that mediates the action of GnRH to stimulate the secretion of the gonadotropic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This receptor mediates its action by association with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Isoform 2 may act as an inhibitor of GnRH-R signaling.

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BioChemical Class

GPCR rhodopsin

UniProt ID

GNRHR_HUMAN

Sequence

MANSASPEQNQNHCSAINNSIPLMQGNLPTLTLSGKIRVTVTFFLFLLSATFNASFLLKL
QKWTQKKEKGKKLSRMKLLLKHLTLANLLETLIVMPLDGMWNITVQWYAGELLCKVLSYL
KLFSMYAPAFMMVVISLDRSLAITRPLALKSNSKVGQSMVGLAWILSSVFAGPQLYIFRM
IHLADSSGQTKVFSQCVTHCSFSQWWHQAFYNFFTFSCLFIIPLFIMLICNAKIIFTLTR
VLHQDPHELQLNQSKNNIPRARLKTLKMTVAFATSFTVCWTPYYVLGIWYWFDPEMLNRL
SDPVNHFFFLFAFLNPCFDPLIYGYFSL

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

HIT2.0 ID

T45C0Q

Drugs and Modes of Action

Top

Approved Drug(s)

[+] 10 Approved Drugs

Abarelix

Drug Info

Approved

Prostate cancer

[2], [3]

Cetrorelix

Drug Info

Approved

Ovarian stimulation

[4], [5]

Degarelix

Drug Info

Approved

Prostate cancer

[6], [7]

Elagolix sodium

Drug Info

Approved

Endometriosis

[8]

Ganirelix

Drug Info

Approved

Ovulation dysfunction

[9], [10]

Gonadorelin

Drug Info

Approved

Hypothalamic hypogonadism

[10], [11]

Leuprorelin acetate

Drug Info

Approved

Prostate cancer

[12]

Nafarelin

Drug Info

Approved

Endometriosis

[10], [13]

Relugolix

Drug Info

Approved

Prostate cancer

[14]

Triptorelin

Drug Info

Approved

Solid tumour/cancer

[10], [15]

Clinical Trial Drug(s)

[+] 8 Clinical Trial Drugs

AEZS-108

Drug Info

Phase 3

Acute lymphoblastic leukaemia

[16]

Elagolix

Drug Info

Phase 3

Uterine fibroids

[17], [18]

GnRH

Drug Info

Phase 3

Female infertility

[19]

ACYLINE

Drug Info

Phase 2

Prostate cancer

[20]

ASP-1707

Drug Info

Phase 2

Endometriosis

[21]

KLH-2109

Drug Info

Phase 2

Endometriosis

[22]

Ozarelix

Drug Info

Phase 2

Prostate disease

[23]

PEP-223/CoVaccine HT

Drug Info

Phase 1/2

Prostate cancer

[24]

Discontinued Drug(s)

[+] 9 Discontinued Drugs

Antide

Drug Info

Discontinued in Phase 2

Prostate hyperplasia

[25], [26]

Gonadimmune

Drug Info

Discontinued in Phase 2

Prostate cancer

[27]

TAK-013

Drug Info

Discontinued in Phase 2

Uterine fibroids

[28], [29]

A-75998

Drug Info

Discontinued in Phase 1

Hormone deficiency

[30]

NBI-42902

Drug Info

Discontinued in Phase 1

Prostate cancer

[31], [32]

Prostate cancer vaccine

Drug Info

Discontinued in Phase 1

Prostate cancer

[33]

Ramorelix

Drug Info

Discontinued in Phase 1

Esophageal cancer

[34]

D-21775

Drug Info

Terminated

Solid tumour/cancer

[36]

D-26344

Drug Info

Terminated

Solid tumour/cancer

[37]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

5-(N,N-hexamethylene)-amiloride

Drug Info

Preclinical

Coronavirus infection

[35]

Mode of Action

[+] 5 Modes of Action

Modulator

[+] 9 Modulator drugs

Abarelix

Drug Info

[38]

Triptorelin

Drug Info

[45]

AEZS-108

Drug Info

[46]

GnRH

Drug Info

[48]

Ozarelix

Drug Info

[23]

Gonadimmune

Drug Info

[53]

D-21775

Drug Info

[48]

detirelix

Drug Info

[61], [62]

Org-30850

Drug Info

[67]

Antagonist

[+] 16 Antagonist drugs

Cetrorelix

Drug Info

[1], [39]

Elagolix sodium

Drug Info

[8]

Ganirelix

Drug Info

[41]

Relugolix

Drug Info

[14]

Elagolix

Drug Info

[47]

ASP-1707

Drug Info

[50]

Antide

Drug Info

[52]

A-75998

Drug Info

[55]

Ramorelix

Drug Info

[57]

AEZS-115

Drug Info

[48]

antarelix

Drug Info

[60]

FD-1

Drug Info

[58]

furan-1

Drug Info

[63]

IN-3

Drug Info

[64]

LXT-101

Drug Info

[66]

[125I]cetrorelix

Drug Info

[70]

Inhibitor

[+] 44 Inhibitor drugs

Degarelix

Drug Info

[40]

ACYLINE

Drug Info

[49]

TAK-013

Drug Info

[54]

NBI-42902

Drug Info

[56]

D-26344

Drug Info

[59]

AN-207

Drug Info

[48]

AZALINE B

Drug Info

[49]

LHRH

Drug Info

[65]

PGlu-His-Trp-Ser-His-D-Tyr-Leu-Arg-Pro-Gly-NH2

Drug Info

[68]

PGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2

Drug Info

[68]

T-98475

Drug Info

[54]

WAY-207024

Drug Info

[69]

[4Aph(CO-(C2H4O)3-C2H4-NH-CO-NH-OCH3)5]degarelix

Drug Info

[71]

[4Aph(CO-NH-(C2H4O)2-C2H5)5]degarelix

Drug Info

[71]

[4Aph(CO-NH-OCH3)5,D-4Aph(CO-NH-OCH3)6]degarelix

Drug Info

[71]

[4Aph(CO-NH-OCH3)5]degarelix

Drug Info

[71]

[4Aph(CO-NH-OH)5]degarelix

Drug Info

[71]

[D-4Aph(CO-NH-(C2H4O)2-C2H5)6]degarelix

Drug Info

[71]

[D-4Aph(CO-NH-OCH3)6]degarelix

Drug Info

[71]

[D-4Aph(CO-NH-OH)6]degarelix

Drug Info

[71]

[D-Dab(CO-NH-OCH3)3]degarelix

Drug Info

[71]

[D-Dab(CO-NH-OH)3]degarelix

Drug Info

[71]

[D-Dap(CO-NH-OCH3)3]degarelix

Drug Info

[71]

[D-Dap(CO-NH-OH)3]degarelix

Drug Info

[71]

[D-Gln3,D-Ncy(isopropyl)7]acyline

Drug Info

[49]

[D-Gln3,D-Ncy(SO,isopropyl)7]acyline

Drug Info

[49]

[D-Gln3,D-Ncy(SO2,isopropyl)7]acyline

Drug Info

[49]

[D-Gln3,Ncy(isopropyl)7]acyline

Drug Info

[49]

[D-Gln3,Ncy(SO,isopropyl)7]acyline

Drug Info

[49]

[D-Gln3,Ncy(SO2,isopropyl)7]acyline

Drug Info

[49]

[D-Ncy(2-naphthyl)1]acyline

Drug Info

[49]

[D-Ncy(isopropyl)7]acyline

Drug Info

[49]

[D-Ncy(methyl)10] acyline

Drug Info

[49]

[D-Ncy(methyl)4]acyline

Drug Info

[49]

[D-Ncy(SO,isopropyl)7]acyline

Drug Info

[49]

[D-Ncy(SO,methyl)10]acyline

Drug Info

[49]

[D-Ncy(SO,methyl)4]acyline

Drug Info

[49]

[Ncy(2-naphthyl)1]acyline

Drug Info

[49]

[Ncy(isopropyl)7]acyline

Drug Info

[49]

[Ncy(methyl)10]acyline

Drug Info

[49]

[Ncy(methyl)4]acyline

Drug Info

[49]

[Ncy(SO,isopropyl)7]acyline

Drug Info

[49]

[Ncy(SO,methyl)10]acyline

Drug Info

[49]

[Ncy(SO,methyl)4]acyline

Drug Info

[49]

Agonist

[+] 4 Agonist drugs

Gonadorelin

Drug Info

[42]

Leuprorelin acetate

Drug Info

[43]

Nafarelin

Drug Info

[44]

KLH-2109

Drug Info

[51]

Modulator (allosteric modulator)

[+] 1 Modulator (allosteric modulator) drugs

5-(N,N-hexamethylene)-amiloride

Drug Info

[58]

Chemical Structure based Activity Landscape of Target

Top

Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

Top

Target-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 2 KEGG Pathways

Neuroactive ligand-receptor interaction

GnRH signaling pathway

NetPath Pathway

[+] 2 NetPath Pathways

IL1 Signaling Pathway

IL2 Signaling Pathway

Panther Pathway

[+] 1 Panther Pathways

Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway

Reactome

[+] 2 Reactome Pathways

Hormone ligand-binding receptors

G alpha (q) signalling events

WikiPathways

[+] 5 WikiPathways

Gastrin-CREB signalling pathway via PKC and MAPK

Peptide GPCRs

GPCR ligand binding

GPCR downstream signaling

GPCRs, Other

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

REF 1

Gonadotropin releasing hormone analogs induce apoptosis by extrinsic pathway involving p53 phosphorylation in primary cell cultures of human prostatic adenocarcinomas. Prostate. 2009 Jul 1;69(10):1025-33.

REF 2

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. (Ligand id: 1188).

REF 3

Abarelix for injectable suspension: first-in-class gonadotropin-releasing hormone antagonist for prostate cancer. Future Oncol. 2006 Dec;2(6):677-96.

REF 4

REF 5

New drugs in development for the treatment of endometriosis. Expert Opin Investig Drugs. 2008 Aug;17(8):1187-202.

REF 6

REF 7

ClinicalTrials.gov (NCT01512472) Firmagon (Degarelix) Intermittent Therapy. U.S. National Institutes of Health.

REF 8

2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.

REF 9

REF 10

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 11

REF 12

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 13

REF 14

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020

REF 15

REF 16

ClinicalTrials.gov (NCT01767155) Study Comparing AEZS-108/ZoptEC (Zoptarelin Doxorubicin in Endometrial Cancer) to Doxorubicin as a Second Line Therapy of Endometrial Cancer. U.S. National Institutesof Health.

REF 17

REF 18

ClinicalTrials.gov (NCT01620528) A Clinical Study to Evaluate the Safety and Efficacy of Elagolix in Subjects With Moderate to Severe Endometriosis-Associated Pain. U.S. National Institutes of Health.

REF 19

Clinical pipeline report, company report or official report of Ferring Pharmaceuticals Inc.

REF 20

ClinicalTrials.gov (NCT02147964) ITT-5 Mechanisms of Spermatogenesis. U.S. National Institutes of Health.

REF 21

ClinicalTrials.gov (NCT01767090) A Study to Assess the Effectiveness and Safety of Different Doses of ASP1707 Compared to Placebo for Endometriosis Associated Pelvic Pain. U.S. National Institutes ofHealth.

REF 22

ClinicalTrials.gov (NCT01533532) A Randomized, Placebo-controlled, Double-blind Study of KLH-2109 in Patients With Endometriosis (2). U.S. National Institutes of Health.

REF 23

Ozarelix, a fourth generation GnRH antagonist, induces apoptosis in hormone refractory androgen receptor negative prostate cancer cells modulating expression and activity of death receptors. Prostate. 2010 Sep 1;70(12):1340-9.

REF 24

ClinicalTrials.gov (NCT00895466) Efficacy and Safety Study of the Therapeutic Vaccine PEP223 in Prostate Cancer Patients. U.S. National Institutes of Health.

REF 25

REF 26

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000763)

REF 27

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007230)

REF 28

REF 29

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800017215)

REF 30

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003694)

REF 31

REF 32

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013539)

REF 33

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014087)

REF 34

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008630)

REF 35

Coronaviruses - drug discovery and therapeutic options. Nat Rev Drug Discov. 2016 May;15(5):327-47.

REF 36

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003256)

REF 37

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013297)

REF 38

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.

REF 39

Gonadotrophin-releasing hormone antagonists for assisted conception. Cochrane Database Syst Rev. 2006 Jul 19;3:CD001750.

REF 40

Iterative approach to the discovery of novel degarelix analogues: substitutions at positions 3, 7, and 8. Part II. J Med Chem. 2005 Jul 28;48(15):4851-60.

REF 41

Age attenuates testosterone secretion driven by amplitude-varying pulses of recombinant human luteinizing hormone during acute gonadotrope inhibiti... J Clin Endocrinol Metab. 2007 Sep;92(9):3626-32.

REF 42

Use of cognitive behavior therapy for functional hypothalamic amenorrhea. Ann N Y Acad Sci. 2006 Dec;1092:114-29.

REF 43

Clinical pipeline report, company report or official report of Takeda (2009).

REF 44

Reversible downregulation of endocrine and germinative testicular function (hormonal castration) in the dog with the GnRH-agonist azagly-nafarelin ... Theriogenology. 2009 Apr 15;71(7):1037-45.

REF 45

Regulation of GnRH I receptor gene expression by the GnRH agonist triptorelin, estradiol, and progesterone in the gonadotroph-derived cell line alphaT3-1. Endocrine. 2006 Aug;30(1):139-44.

REF 46

Stability of cytotoxic luteinizing hormone-releasing hormone conjugate (AN-152) containing doxorubicin 14-O-hemiglutarate in mouse and human serum in vitro: implications for the design of preclinicalstudies. Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):829-34.

REF 47

Elagolix, a novel, orally bioavailable GnRH antagonist under investigation for the treatment of endometriosis-related pain. Womens Health (Lond Engl). 2015 Jan;11(1):19-28.

REF 48

REF 49

Structure-activity relationship studies of gonadotropin-releasing hormone antagonists containing S-aryl/alkyl norcysteines and their oxidized deriv... J Med Chem. 2007 May 3;50(9):2067-77.

REF 50

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800032657)

REF 51

Clinical pipeline report, company report or official report of Avarx.

REF 52

Antide (Nal-Lys GnRH antagonist) suppression of pituitary-testicular function and sexual behavior in group-living rhesus monkeys. Physiol Behav. 1991 Aug;50(2):429-35.

REF 53

A novel retro-inverso gonadotropin-releasing hormone (GnRH) immunogen elicits antibodies that neutralize the activity of native GnRH. Endocrinology. 2003 Jul;144(7):3262-9.

REF 54

Non-peptide gonadotropin-releasing hormone receptor antagonists. J Med Chem. 2008 Jun 26;51(12):3331-48.

REF 55

Physicochemical properties of A-75998, an antagonist of luteinizing hormone releasing hormone. J Pharm Sci. 1995 Aug;84(8):953-8.

REF 56

Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. J Med Chem. 2008 Dec 11;51(23):7478-85.

REF 57

Effects of the luteinizing-hormone-releasing hormone (LHRH) antagonist ramorelix (hoe013) and the LHRH agonist buserelin on dimethylbenz[]anthracene-induced mammary carcinoma: studies with slow-release formulations. J Cancer Res Clin Oncol. 1993;119(8):457-62.

REF 58

Amiloride derivatives and a nonpeptidic antagonist bind at two distinct allosteric sites in the human gonadotropin-releasing hormone receptor. Mol Pharmacol. 2008 Jun;73(6):1808-15.

REF 59

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003256)

REF 60

Characterization of gonadotropin-releasing hormone analogs based on a sensitive cellular luciferase reporter gene assay. Anal Biochem. 1997 Aug 15;251(1):17-23.

REF 61

Inhibition of follicular development by a potent antagonistic analog of gonadotropin-releasing hormone (detirelix). J Clin Endocrinol Metab. 1991 Apr;72(4):927-33.

REF 62

Gonadotropin-releasing hormone receptor-targeted paclitaxel-degarelix conjugate: synthesis and in vitro evaluation.J Pept Sci.2015 Jul;21(7):569-76.

REF 63

Biological characterization of a novel, orally active small molecule gonadotropin-releasing hormone (GnRH) antagonist using castrated and intact rats. J Pharmacol Exp Ther. 2003 May;305(2):688-95.

REF 64

Rescue of hypogonadotropic hypogonadism-causing and manufactured GnRH receptor mutants by a specific protein-folding template: misrouted proteins as a novel disease etiology and therapeutic target. JClin Endocrinol Metab. 2002 Jul;87(7):3255-62.

REF 65

Discovery of a novel, potent, and orally active nonpeptide antagonist of the human luteinizing hormone-releasing hormone (LHRH) receptor. J Med Chem. 1998 Oct 22;41(22):4190-5.

REF 66

In vivo characterization of a novel GnRH (gonadotropin-releasing hormone) antagonist, LXT-101, in normal male rats. Regul Pept. 2006 Sep 11;136(1-3):122-9.

REF 67

In vivo effects of a potent GnRH antagonist ORG 30850: physiologic evidence that down-regulation of GnRH receptors does not occur. J Soc Gynecol Investig. 1994 Oct-Dec;1(4):290-6.

REF 68

Overlapping, nonidentical binding sites of different classes of nonpeptide antagonists for the human gonadotropin-releasing hormone receptor. J Med Chem. 2006 Jan 26;49(2):637-47.

REF 69

Synthesis and biological evaluation of piperazinyl heterocyclic antagonists of the gonadotropin releasing hormone (GnRH) receptor. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2512-5.

REF 70

Residues within transmembrane helices 2 and 5 of the human gonadotropin-releasing hormone receptor contribute to agonist and antagonist binding. Mol Endocrinol. 2000 Jul;14(7):1099-115.

REF 71

Novel analogues of degarelix incorporating hydroxy-, methoxy-, and pegylated-urea moieties at positions 3, 5, 6 and the N-terminus. Part III. J Med Chem. 2006 Jun 15;49(12):3536-43.

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