Target Information
Target General Infomation | |||||
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Target ID |
T60631
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Former ID |
TTDS00348
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Target Name |
Proto-oncogene tyrosine-protein kinase receptor ret
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Gene Name |
RET
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Synonyms |
C-ret; RET receptor tyrosine kinase; RET
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Target Type |
Successful
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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.
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BioChemical Class |
Kinase
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Target Validation |
T60631
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UniProt ID | |||||
EC Number |
EC 2.7.10.1
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Sequence |
MAKATSGAAGLRLLLLLLLPLLGKVALGLYFSRDAYWEKLYVDQAAGTPLLYVHALRDAP
EEVPSFRLGQHLYGTYRTRLHENNWICIQEDTGLLYLNRSLDHSSWEKLSVRNRGFPLLT VYLKVFLSPTSLREGECQWPGCARVYFSFFNTSFPACSSLKPRELCFPETRPSFRIRENR PPGTFHQFRLLPVQFLCPNISVAYRLLEGEGLPFRCAPDSLEVSTRWALDREQREKYELV AVCTVHAGAREEVVMVPFPVTVYDEDDSAPTFPAGVDTASAVVEFKRKEDTVVATLRVFD ADVVPASGELVRRYTSTLLPGDTWAQQTFRVEHWPNETSVQANGSFVRATVHDYRLVLNR NLSISENRTMQLAVLVNDSDFQGPGAGVLLLHFNVSVLPVSLHLPSTYSLSVSRRARRFA QIGKVCVENCQAFSGINVQYKLHSSGANCSTLGVVTSAEDTSGILFVNDTKALRRPKCAE LHYMVVATDQQTSRQAQAQLLVTVEGSYVAEEAGCPLSCAVSKRRLECEECGGLGSPTGR CEWRQGDGKGITRNFSTCSPSTKTCPDGHCDVVETQDINICPQDCLRGSIVGGHEPGEPR GIKAGYGTCNCFPEEEKCFCEPEDIQDPLCDELCRTVIAAAVLFSFIVSVLLSAFCIHCY HKFAHKPPISSAEMTFRRPAQAFPVSYSSSGARRPSLDSMENQVSVDAFKILEDPKWEFP RKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLK QVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDH PDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVY EEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERL FNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAA STPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRA DGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS |
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Structure |
1XPD; 2IVS; 2IVT; 2IVU; 2IVV; 2X2K; 2X2L; 2X2M; 2X2U; 4CKI; 4CKJ; 4UX8
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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) | |||||
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 524880 | ClinicalTrials.gov (NCT02219711) Phase 1/1b Study of MGCD516 in Patients With Advanced Cancer. U.S. National Institutes of Health. | ||||
Ref 536998 | 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 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 528527 | Bioorg 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 528954 | 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 530673 | Bioorg 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 531337 | 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 531435 | 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 531471 | 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 535832 | 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 536474 | 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 536998 | 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. |
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