Target Information
Target General Information | Top | |||||
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Target ID |
T60631
(Former ID: TTDS00348)
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Target Name |
Proto-oncogene c-Ret (RET)
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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
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Gene Name |
RET
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 6 Target-related Diseases | + | ||||
1 | Colorectal cancer [ICD-11: 2B91] | |||||
2 | Lung cancer [ICD-11: 2C25] | |||||
3 | Mature B-cell lymphoma [ICD-11: 2A85] | |||||
4 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
5 | Thrombocytopenia [ICD-11: 3B64] | |||||
6 | Thyroid cancer [ICD-11: 2D10] | |||||
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.
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BioChemical Class |
Kinase
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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 Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
HIT2.0 ID | T34WFL |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 6 Approved Drugs | + | ||||
1 | Ponatinib | Drug Info | Approved | Acute lymphoblastic leukaemia | [2], [3] | |
2 | Pralsetinib | Drug Info | Approved | Non-small-cell lung cancer | [4] | |
3 | Regorafenib | Drug Info | Approved | Metastatic colorectal cancer | [3], [5] | |
4 | Romiplostim | Drug Info | Approved | Thrombocytopenia | [6], [7] | |
5 | Selpercatinib | Drug Info | Approved | Non-small-cell lung cancer | [8] | |
6 | Vandetanib | Drug Info | Approved | Solid tumour/cancer | [9], [10] | |
Clinical Trial Drug(s) | [+] 6 Clinical Trial Drugs | + | ||||
1 | MGCD516 | Drug Info | Phase 2/3 | Solid tumour/cancer | [11] | |
2 | CEP-32496 | Drug Info | Phase 1/2 | Solid tumour/cancer | [12], [13] | |
3 | TPX-0046 | Drug Info | Phase 1/2 | Solid tumour/cancer | [14] | |
4 | BOS172738 | Drug Info | Phase 1 | Solid tumour/cancer | [15] | |
5 | GSK3179106 | Drug Info | Phase 1 | Inflammatory bowel disease | [16] | |
6 | tamatinib | Drug Info | Clinical trial | Solid tumour/cancer | [17] | |
Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | CEP-751 | Drug Info | Terminated | Neurodegenerative disorder | [18] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Modulator | [+] 2 Modulator drugs | + | ||||
1 | Ponatinib | Drug Info | [19] | |||
2 | Regorafenib | Drug Info | [19] | |||
Inhibitor | [+] 51 Inhibitor drugs | + | ||||
1 | Pralsetinib | Drug Info | [4] | |||
2 | Romiplostim | Drug Info | [1] | |||
3 | Selpercatinib | Drug Info | [8] | |||
4 | Vandetanib | Drug Info | [20], [21] | |||
5 | MGCD516 | Drug Info | [22] | |||
6 | MGCD516 | Drug Info | [23] | |||
7 | CEP-32496 | Drug Info | [24] | |||
8 | TPX-0046 | Drug Info | [25] | |||
9 | BOS172738 | Drug Info | [26] | |||
10 | GSK3179106 | Drug Info | [16] | |||
11 | tamatinib | Drug Info | [17] | |||
12 | Benzo(b)carbazol-11-one compound 1 | Drug Info | [27] | |||
13 | Benzo(b)carbazol-11-one compound 2 | Drug Info | [27] | |||
14 | Carboxamide derivative 4 | Drug Info | [27] | |||
15 | Dihydropyridine compound 1 | Drug Info | [27] | |||
16 | Dihydropyridine compound 2 | Drug Info | [27] | |||
17 | Dihydropyridine compound 3 | Drug Info | [27] | |||
18 | Dihydropyridine compound 4 | Drug Info | [27] | |||
19 | Dihydropyridine compound 5 | Drug Info | [27] | |||
20 | Dihydropyridine compound 6 | Drug Info | [27] | |||
21 | Pyrazolo[3,4-d]pyrimidine derivative 5 | Drug Info | [27] | |||
22 | Pyrazolo[3,4-d]pyrimidine derivative 6 | Drug Info | [27] | |||
23 | Pyrazolo[3,4-d]pyrimidine derivative 7 | Drug Info | [27] | |||
24 | Pyrazolo[3,4-d]pyrimidine derivative 8 | Drug Info | [27] | |||
25 | Pyridine derivative 18 | Drug Info | [27] | |||
26 | Pyridine derivative 19 | Drug Info | [27] | |||
27 | Pyridine derivative 20 | Drug Info | [27] | |||
28 | Pyridine derivative 21 | Drug Info | [27] | |||
29 | Pyridine derivative 22 | Drug Info | [27] | |||
30 | Pyrrolo-pyridinone derivative 1 | Drug Info | [27] | |||
31 | Pyrrolo-pyridinone derivative 2 | Drug Info | [27] | |||
32 | Pyrrolo-pyridinone derivative 3 | Drug Info | [27] | |||
33 | Pyrrolo-pyridinone derivative 4 | Drug Info | [27] | |||
34 | Pyrrolo-pyrimidine derivative 2 | Drug Info | [27] | |||
35 | Pyrrolo-pyrimidine derivative 3 | Drug Info | [27] | |||
36 | Pyrrolo-pyrimidine derivative 4 | Drug Info | [27] | |||
37 | Pyrrolo-pyrimidine derivative 5 | Drug Info | [27] | |||
38 | Pyrrolo-pyrimidine derivative 6 | Drug Info | [27] | |||
39 | Quinazoline derivative 14 | Drug Info | [27] | |||
40 | Quinazoline derivative 15 | Drug Info | [27] | |||
41 | Quinazoline derivative 16 | Drug Info | [27] | |||
42 | CEP-751 | Drug Info | [28] | |||
43 | (E)-3-(4-hydroxybenzylidene)indolin-2-one | Drug Info | [1] | |||
44 | (Z)-3-((1H-pyrrol-2-yl)methylene)indolin-2-one | Drug Info | [1] | |||
45 | (Z)-5-Amino-3-(4-methoxybenzylidene)indolin-2-one | Drug Info | [1] | |||
46 | AST-487 | Drug Info | [29] | |||
47 | GW-559768X | Drug Info | [22] | |||
48 | ITRI-305 | Drug Info | [22] | |||
49 | PMID21493067C1d | Drug Info | [30] | |||
50 | PMID21561767C8h | Drug Info | [31] | |||
51 | TG-100435 | Drug Info | [32] |
Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"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 |
Co-Targets | Top | |||||
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Co-Targets |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
Target Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Profiles in Patients | Top | |||||
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Target Expression Profile (TEP) | ||||||
Drug Resistance Mutation (DRM) |
Target Affiliated Biological Pathways | Top | |||||
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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 | Top | |||||
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Target Validation |
References | Top | |||||
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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 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020 | |||||
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: 5891). | |||||
REF 6 | 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 7 | 2008 FDA drug approvals. Nat Rev Drug Discov. 2009 Feb;8(2):93-6. | |||||
REF 8 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020 | |||||
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: 5717). | |||||
REF 10 | 2011 FDA drug approvals. Nat Rev Drug Discov. 2012 Feb 1;11(2):91-4. | |||||
REF 11 | ClinicalTrials.gov (NCT04887870) Study of Sitravatinib With or Without Other Anticancer Therapies Receiving Clinical Benefit From Parent Study. U.S. National Institutes of Health. | |||||
REF 12 | 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 13 | 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 14 | ClinicalTrials.gov (NCT04161391) Study of TPX-0046, A RET/SRC Inhibitor in Adult Subjects With Advanced Solid Tumors Harboring RET Fusions or Mutations. U.S. National Institutes of Health. | |||||
REF 15 | ClinicalTrials.gov (NCT03780517) Safety, Efficacy, and Tolerability of BOS172738 in Patients With Advanced Rearranged During Transfection (RET) Gene-Altered Tumors. U.S. National Institutes of Health. | |||||
REF 16 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 17 | 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 18 | 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 19 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
REF 20 | 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 21 | Clinical pipeline report, company report or official report of AstraZeneca (2009). | |||||
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 | 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 24 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 25 | Clinical pipeline report, company report or official report of Turning Point Therapeutics. | |||||
REF 26 | National Cancer Institute Drug Dictionary (drug name Zeteletinib). | |||||
REF 27 | RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99. | |||||
REF 28 | 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 29 | 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 30 | 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 31 | 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 32 | 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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