Target General Infomation
Target ID
T60631 (Former ID: TTDS00348)
Target Name
Proto-oncogene c-Ret (RET)
Synonyms
RET51; RET receptor tyrosine kinase; RET mutant Y791F; RET mutant V804M; RET mutant V804L; RET mutant S891A; RET mutant M918T; RET mutant G691S; Proto-oncogene tyrosine-protein kinase receptor Ret; PTC; Cadherin family member 12; CDHR16; CDHF12; C-ret
Gene Name
RET
Target Type
Successful target
[1]
Disease [+] 4 Target-related Diseases +
1 Colorectal cancer [ICD-11: 2B91]
2 Mature B-cell lymphoma [ICD-11: 2A85]
3 Solid tumour/cancer [ICD-11: 2A00-2F9Z]
4 Thrombocytopenia [ICD-11: 3B64]
Function
Phosphorylates PTK2/FAK1. Regulates both cell death/survival balance and positional information. Required for the molecular mechanisms orchestration during intestine organogenesis; involved in the development of enteric nervous system and renal organogenesis during embryonic life, and promotes the formation of Peyer's patch-like structures, a major component of the gut-associated lymphoid tissue. Modulates cell adhesion via its cleavage by caspase in sympathetic neurons and mediates cell migration in an integrin (e. g. ITGB1 and ITGB3)-dependent manner. Involved in the development of the neural crest. Active in the absence of ligand, triggering apoptosis through a mechanism that requires receptor intracellular caspase cleavage. Acts as a dependence receptor; in the presence of the ligand GDNF in somatotrophs (within pituitary), promotes survival and down regulates growth hormone (GH) production, but triggers apoptosis in absence of GDNF. Regulates nociceptor survival and size. Triggers the differentiation of rapidly adapting (RA) mechanoreceptors. Mediator of several diseases such as neuroendocrine cancers; these diseases are characterized by aberrant integrins-regulated cell migration. Mediates, through interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem which induces inhibition of food-intake. Activates MAPK- and AKT-signaling pathways. Isoform 1 in complex with GFRAL induces higher activation of MAPK-signaling pathway than isoform 2 in complex with GFRAL. Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation upon binding with glial cell derived neurotrophic factor family ligands.
BioChemical Class
Kinase
UniProt ID
RET_HUMAN
EC Number
EC 2.7.10.1
Sequence
MAKATSGAAGLRLLLLLLLPLLGKVALGLYFSRDAYWEKLYVDQAAGTPLLYVHALRDAP
EEVPSFRLGQHLYGTYRTRLHENNWICIQEDTGLLYLNRSLDHSSWEKLSVRNRGFPLLT
VYLKVFLSPTSLREGECQWPGCARVYFSFFNTSFPACSSLKPRELCFPETRPSFRIRENR
PPGTFHQFRLLPVQFLCPNISVAYRLLEGEGLPFRCAPDSLEVSTRWALDREQREKYELV
AVCTVHAGAREEVVMVPFPVTVYDEDDSAPTFPAGVDTASAVVEFKRKEDTVVATLRVFD
ADVVPASGELVRRYTSTLLPGDTWAQQTFRVEHWPNETSVQANGSFVRATVHDYRLVLNR
NLSISENRTMQLAVLVNDSDFQGPGAGVLLLHFNVSVLPVSLHLPSTYSLSVSRRARRFA
QIGKVCVENCQAFSGINVQYKLHSSGANCSTLGVVTSAEDTSGILFVNDTKALRRPKCAE
LHYMVVATDQQTSRQAQAQLLVTVEGSYVAEEAGCPLSCAVSKRRLECEECGGLGSPTGR
CEWRQGDGKGITRNFSTCSPSTKTCPDGHCDVVETQDINICPQDCLRGSIVGGHEPGEPR
GIKAGYGTCNCFPEEEKCFCEPEDIQDPLCDELCRTVIAAAVLFSFIVSVLLSAFCIHCY
HKFAHKPPISSAEMTFRRPAQAFPVSYSSSGARRPSLDSMENQVSVDAFKILEDPKWEFP
RKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLK
QVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDH
PDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVY
EEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERL
FNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAA
STPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRA
DGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS
Drugs and Modes of Action
Approved Drug(s) [+] 4 Approved Drugs +
1 Ponatinib Drug Info Approved Acute lymphoblastic leukaemia [2], [3]
2 Regorafenib Drug Info Approved Metastatic colorectal cancer [3], [4]
3 Romiplostim Drug Info Approved Thrombocytopenia [5], [6]
4 Vandetanib Drug Info Approved Solid tumour/cancer [7], [8]
Clinical Trial Drug(s) [+] 6 Clinical Trial Drugs +
1 CEP-32496 Drug Info Phase 1/2 Solid tumour/cancer [9], [10]
2 MGCD516 Drug Info Phase 1/2 Solid tumour/cancer [11]
3 BLU-667 Drug Info Phase 1 Solid tumour/cancer [11]
4 GSK3179106 Drug Info Phase 1 Inflammatory bowel disease [12]
5 LOXO-292 Drug Info Phase 1 Solid tumour/cancer [11]
6 tamatinib Drug Info Clinical trial Solid tumour/cancer [13]
Discontinued Drug(s) [+] 1 Discontinued Drugs +
1 CEP-751 Drug Info Terminated Neurodegenerative disorder [14]
Mode of Action [+] 2 Modes of Action +
Modulator [+] 2 Modulator drugs +
1 Ponatinib Drug Info [15]
2 Regorafenib Drug Info [15]
Inhibitor [+] 49 Inhibitor drugs +
1 Romiplostim Drug Info [1]
2 Vandetanib Drug Info [16], [17]
3 CEP-32496 Drug Info [11]
4 MGCD516 Drug Info [18]
5 BLU-667 Drug Info [11]
6 GSK3179106 Drug Info [12]
7 LOXO-292 Drug Info [11]
8 tamatinib Drug Info [13]
9 Benzo(b)carbazol-11-one compound 1 Drug Info [19]
10 Benzo(b)carbazol-11-one compound 2 Drug Info [19]
11 Carboxamide derivative 4 Drug Info [19]
12 Dihydropyridine compound 1 Drug Info [19]
13 Dihydropyridine compound 2 Drug Info [19]
14 Dihydropyridine compound 3 Drug Info [19]
15 Dihydropyridine compound 4 Drug Info [19]
16 Dihydropyridine compound 5 Drug Info [19]
17 Dihydropyridine compound 6 Drug Info [19]
18 Pyrazolo[3,4-d]pyrimidine derivative 5 Drug Info [19]
19 Pyrazolo[3,4-d]pyrimidine derivative 6 Drug Info [19]
20 Pyrazolo[3,4-d]pyrimidine derivative 7 Drug Info [19]
21 Pyrazolo[3,4-d]pyrimidine derivative 8 Drug Info [19]
22 Pyridine derivative 18 Drug Info [19]
23 Pyridine derivative 19 Drug Info [19]
24 Pyridine derivative 20 Drug Info [19]
25 Pyridine derivative 21 Drug Info [19]
26 Pyridine derivative 22 Drug Info [19]
27 Pyrrolo-pyridinone derivative 1 Drug Info [19]
28 Pyrrolo-pyridinone derivative 2 Drug Info [19]
29 Pyrrolo-pyridinone derivative 3 Drug Info [19]
30 Pyrrolo-pyridinone derivative 4 Drug Info [19]
31 Pyrrolo-pyrimidine derivative 2 Drug Info [19]
32 Pyrrolo-pyrimidine derivative 3 Drug Info [19]
33 Pyrrolo-pyrimidine derivative 4 Drug Info [19]
34 Pyrrolo-pyrimidine derivative 5 Drug Info [19]
35 Pyrrolo-pyrimidine derivative 6 Drug Info [19]
36 Quinazoline derivative 14 Drug Info [19]
37 Quinazoline derivative 15 Drug Info [19]
38 Quinazoline derivative 16 Drug Info [19]
39 CEP-751 Drug Info [20]
40 (E)-3-(4-hydroxybenzylidene)indolin-2-one Drug Info [1]
41 (Z)-3-((1H-pyrrol-2-yl)methylene)indolin-2-one Drug Info [1]
42 (Z)-5-Amino-3-(4-methoxybenzylidene)indolin-2-one Drug Info [1]
43 AST-487 Drug Info [21]
44 GW-559768X Drug Info [22]
45 ITRI-305 Drug Info [22]
46 MG-516 Drug Info [22]
47 PMID21493067C1d Drug Info [23]
48 PMID21561767C8h Drug Info [24]
49 TG-100435 Drug Info [25]
Target Regulators
Target-regulating microRNAs
Target-interacting Proteins
Target Profiles in Patients
Target Expression
 Profile (TEP)
Drug Resistance
 Mutation (DRM)
Target Affiliated Biological Pathways
KEGG Pathway [+] 4 KEGG Pathways +
1 Endocytosis
2 Pathways in cancer
3 Thyroid cancer
4 Central carbon metabolism in cancer
PID Pathway [+] 2 PID Pathways +
1 Signaling events regulated by Ret tyrosine kinase
2 Posttranslational regulation of adherens junction stability and dissassembly
WikiPathways [+] 2 WikiPathways +
1 SIDS Susceptibility Pathways
2 Dopaminergic Neurogenesis
Target-Related Models and Studies
Target Validation
References
REF 1 Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors. Bioorg Med Chem. 2010 Feb 15;18(4):1482-96.
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: 5890).
REF 3 Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
REF 4 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: 5891).
REF 5 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: 6974).
REF 6 2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6.
REF 7 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: 5717).
REF 8 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
REF 9 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: 7880).
REF 10 ClinicalTrials.gov (NCT01877811) CEP-32496 in Patients With Advanced Solid Tumors in Phase 1 and Advanced Melanoma and Metastatic Colorectal Cancer in Phase 2. U.S. National Institutes of Health.
REF 11 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 12 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
REF 13 Developmental toxicity associated with receptor tyrosine kinase Ret inhibition in reproductive toxicity testing. Birth Defects Res A Clin Mol Teratol. 2009 Feb;85(2):130-6.
REF 14 Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008742)
REF 15 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 16 A comparison of physicochemical property profiles of marketed oral drugs and orally bioavailable anti-cancer protein kinase inhibitors in clinical development. Curr Top Med Chem. 2007;7(14):1408-22.
REF 17 Clinical pipeline report, company report or official report of AstraZeneca (2009).
REF 18 Role and relevance of TrkB mutations and expression in non-small cell lung cancer. Clin Cancer Res. 2011 May 1;17(9):2638-45.
REF 19 RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99.
REF 20 CEP-701 and CEP-751 inhibit constitutively activated RET tyrosine kinase activity and block medullary thyroid carcinoma cell growth. Cancer Res. 2003 Sep 1;63(17):5559-63.
REF 21 The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Res. 2007 Jul 15;67(14):6956-64.
REF 22 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: 2185).
REF 23 In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. Bioorg Med Chem Lett. 2011 May 15;21(10):2958-61.
REF 24 Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3743-8.
REF 25 Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine--a potent, orally active Src kinas... Bioorg Med Chem Lett. 2007 Feb 1;17(3):602-8.

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