Target General Infomation
Target ID
T60631
Former ID
TTDS00348
Target Name
Proto-oncogene tyrosine-protein kinase receptor ret
Gene Name
RET
Synonyms
C-ret; RET receptor tyrosine kinase; RET
Target Type
Successful
Disease Acute lymphoblastic leukemia [ICD9: 204.0, 556; ICD10: C91.0]
Cancer [ICD9: 140-229; ICD10: C00-C96]
Metastatic colorectal cancer [ICD9: 153, 154; ICD10: C18-C21]
Neurodegenerative disease [ICD9: 330-337; ICD10: G30-G32]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Thyroid cancer [ICD9: 140-229, 193; ICD10: C73]
Function
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. 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.
BioChemical Class
Kinase
Target Validation
T60631
UniProt ID
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
Structure
1XPD; 2IVS; 2IVT; 2IVU; 2IVV; 2X2K; 2X2L; 2X2M; 2X2U; 4CKI; 4CKJ; 4UX8
Drugs and Mode of Action
Drug(s) Ponatinib Drug Info Approved Acute lymphoblastic leukemia [532210], [541188]
Regorafenib Drug Info Approved Metastatic colorectal cancer [532210], [541189]
Vandetanib Drug Info Approved Solid tumours [531783], [541055]
MGCD516 Drug Info Phase 1 Solid tumours [524880]
tamatinib Drug Info Clinical trial Solid tumours [536998]
CEP-751 Drug Info Terminated Neurodegenerative disease [546524]
Inhibitor (E)-3-(4-hydroxybenzylidene)indolin-2-one Drug Info [530673]
(Z)-3-((1H-pyrrol-2-yl)methylene)indolin-2-one Drug Info [530673]
(Z)-5-Amino-3-(4-methoxybenzylidene)indolin-2-one Drug Info [530673]
AST-487 Drug Info [528954]
CEP-751 Drug Info [535832]
compound 1d Drug Info [531435]
compound 8h Drug Info [531471]
GW-559768X Drug Info [543572]
ITRI-305 Drug Info [543572]
MG-516 Drug Info [543572]
MGCD516 Drug Info [531337]
SEMAXINIB Drug Info [530673]
tamatinib Drug Info [536998]
TG-100435 Drug Info [528527]
Vandetanib Drug Info [536474], [550288]
Modulator Ponatinib Drug Info [551871]
Regorafenib Drug Info [551871]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
DRM DRM Info
Pathways
KEGG Pathway Endocytosis
Pathways in cancer
Thyroid cancer
Central carbon metabolism in cancer
Pathway Interaction Database Signaling events regulated by Ret tyrosine kinase
Posttranslational regulation of adherens junction stability and dissassembly
WikiPathways SIDS Susceptibility Pathways
Dopaminergic Neurogenesis
References
Ref 524880ClinicalTrials.gov (NCT02219711) Phase 1/1b Study of MGCD516 in Patients With Advanced Cancer. U.S. National Institutes of Health.
Ref 5317832011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4.
Ref 532210Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
Ref 536998Developmental 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 541055(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 541188(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 541189(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 546524Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008742)
Ref 528527Bioorg Med Chem Lett. 2007 Feb 1;17(3):602-8. Epub 2006 Nov 7.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 kinase inhibitor with anti-tumor activity in preclinical assays.
Ref 528954The 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 530673Bioorg Med Chem. 2010 Feb 15;18(4):1482-96. Epub 2010 Jan 11.Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors.
Ref 531337Role and relevance of TrkB mutations and expression in non-small cell lung cancer. Clin Cancer Res. 2011 May 1;17(9):2638-45.
Ref 531435In 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 531471Discovery 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 535832CEP-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 536474A 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 536998Developmental 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 543572(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 550288Clinical pipeline report, company report or official report of AstraZeneca (2009).
Ref 551871Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

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