ret proto-oncogene | Type XIV RTKs: RET | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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ret proto-oncogene

Target id: 2185

Nomenclature: ret proto-oncogene

Abbreviated Name: Ret

Family: Type XIV RTKs: RET

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1072 10q11.21 RET ret proto-oncogene
Mouse 1 1073 6 E3-F1 Ret ret proto-oncogene
Rat 1 1115 4 q42 Ret ret proto-oncogene
Previous and Unofficial Names
cadherin-related family member 16 | CDHF12 | CDHR16 | c-Ret | HSCR1, MEN2A, MTC1, MEN2B | RET51 | RET9
Database Links
BRENDA
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF NON-PHOSPHORYLATED RET TYROSINE KINASE DOMAIN
PDB Id:  2IVS
Resolution:  2.0Å
Species:  Human
References:  13
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF PHOSPHORYLATED RET TYROSINE KINASE DOMAIN WITH INHIBITOR
PDB Id:  2X2L
Resolution:  2.0Å
Species:  Human
References:  16
Enzyme Reaction
EC Number: 2.7.10.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
quizartinib Hs Inhibition 8.0 pKd 6
pKd 8.0 (Kd 9.9x10-9 M) [6]
RG-1530 Hs Inhibition 7.7 pKd 20
pKd 7.7 (Kd 2.2x10-8 M) [20]
vandetanib Hs Inhibition 7.5 pKd 8
pKd 7.5 (Kd 3.4x10-8 M) [8]
compound 8h [PMID: 21561767] Hs Inhibition 9.7 pIC50 18
pIC50 9.7 (IC50 2x10-10 M) [18]
BLU-667 Hs Inhibition 9.4 pIC50 17
pIC50 9.4 (IC50 4x10-10 M) [17]
Description: In a biochemical assay.
sunitinib Hs Inhibition 8.8 pIC50 12
pIC50 8.8 (IC50 1.7x10-9 M) [12]
gilteritinib Hs Inhibition ~8.8 pIC50 14
pIC50 ~8.8 (IC50 ~1.7x10-9 M) [14]
tamatinib Hs Inhibition 8.3 pIC50 7
pIC50 8.3 (IC50 5x10-9 M) [7]
CEP-11981 Hs Inhibition 8.3 pIC50 11
pIC50 8.3 (IC50 5x10-9 M) [11]
ponatinib Hs Inhibition 8.2 pIC50 15
pIC50 8.2 (IC50 7x10-9 M) [15]
KBP-7018 Hs Inhibition 8.1 pIC50 10
pIC50 8.1 (IC50 7.6x10-9 M) [10]
cabozantinib Hs Inhibition 8.0 pIC50 17
pIC50 8.0 (IC50 1.1x10-8 M) [17]
Description: In a biochemical assay.
sorafenib Hs Inhibition 7.9 pIC50 12
pIC50 7.9 (IC50 1.4x10-8 M) [12]
apatinib Hs Inhibition 7.9 pIC50 19
pIC50 7.9 (IC50 1.3x10-8 M) [19]
Description: Assay used apatinib mesylate (YN968D1)
LOXO-292 Hs Inhibition 7.8 pIC50 4
pIC50 7.8 (IC50 1.4x10-8 M) [4]
compound 1d [PMID: 21493067] Hs Inhibition 7.7 pIC50 22
pIC50 7.7 (IC50 1.9x10-8 M) [22]
vandetanib Hs Inhibition 7.0 – 8.4 pIC50 5,17
pIC50 8.4 (IC50 4x10-9 M) [17]
Description: In a biochemical assay.
pIC50 7.0 (IC50 1x10-7 M) [5]
tafetinib Hs Inhibition 7.2 pIC50 21
pIC50 7.2 (IC50 6.81x10-8 M) [21]
Description: In a radiometric biochemical protein kinase assay.
lucitanib Hs Inhibition 6.7 pIC50 24
pIC50 6.7 (IC50 2x10-7 M) [24]
AST-487 Hs Inhibition 6.1 pIC50 1
pIC50 6.1 (IC50 8.8x10-7 M) [1]
Description: In vitro inhibition of wild type RET.
linifanib Hs Inhibition 5.7 pIC50 2
pIC50 5.7 (IC50 1.9x10-6 M) [2]
Inhibitor Comments
Note that sorafenib is a multi-target kinase inhibitor. Kinase targets include PDGFRβ, BRAF, RAF, KIT, FLT3 and VEGF receptors.
Sunitinib inhibits a range of additional kinases, including platelet-derived growth factor receptora α and β (PDGFRα, PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3) and colony stimulating factor receptor Type 1 (CSF-1R).
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 8,23

Key to terms and symbols Click column headers to sort
Target used in screen: RET
Ligand Sp. Type Action Value Parameter
foretinib Hs Inhibitor Inhibition 9.1 pKd
tamatinib Hs Inhibitor Inhibition 8.4 pKd
PP-242 Hs Inhibitor Inhibition 8.3 pKd
cediranib Hs Inhibitor Inhibition 8.2 pKd
quizartinib Hs Inhibitor Inhibition 8.1 pKd
JNJ-28312141 Hs Inhibitor Inhibition 8.0 pKd
sorafenib Hs Inhibitor Inhibition 7.9 pKd
sunitinib Hs Inhibitor Inhibition 7.9 pKd
motesanib Hs Inhibitor Inhibition 7.8 pKd
staurosporine Hs Inhibitor Inhibition 7.8 pKd
Target used in screen: RET(M918T)
Ligand Sp. Type Action Value Parameter
foretinib Hs Inhibitor Inhibition 9.2 pKd
quizartinib Hs Inhibitor Inhibition 8.5 pKd
PP-242 Hs Inhibitor Inhibition 8.4 pKd
tamatinib Hs Inhibitor Inhibition 8.4 pKd
AST-487 Hs Inhibitor Inhibition 8.4 pKd
JNJ-28312141 Hs Inhibitor Inhibition 8.2 pKd
sorafenib Hs Inhibitor Inhibition 8.1 pKd
cediranib Hs Inhibitor Inhibition 8.1 pKd
vandetanib Hs Inhibitor Inhibition 7.8 pKd
lestaurtinib Hs Inhibitor Inhibition 7.8 pKd
Target used in screen: RET(V804L)
Ligand Sp. Type Action Value Parameter
JNJ-28312141 Hs Inhibitor Inhibition 8.9 pKd
foretinib Hs Inhibitor Inhibition 8.8 pKd
tamatinib Hs Inhibitor Inhibition 8.7 pKd
AST-487 Hs Inhibitor Inhibition 8.4 pKd
lestaurtinib Hs Inhibitor Inhibition 8.2 pKd
tozasertib Hs Inhibitor Inhibition 8.1 pKd
sunitinib Hs Inhibitor Inhibition 8.1 pKd
quizartinib Hs Inhibitor Inhibition 7.9 pKd
staurosporine Hs Inhibitor Inhibition 7.8 pKd
SU-14813 Hs Inhibitor Inhibition 7.7 pKd
Target used in screen: RET(V804M)
Ligand Sp. Type Action Value Parameter
JNJ-28312141 Hs Inhibitor Inhibition 9.1 pKd
foretinib Hs Inhibitor Inhibition 8.6 pKd
tamatinib Hs Inhibitor Inhibition 8.5 pKd
AST-487 Hs Inhibitor Inhibition 8.5 pKd
lestaurtinib Hs Inhibitor Inhibition 8.3 pKd
sunitinib Hs Inhibitor Inhibition 8.2 pKd
quizartinib Hs Inhibitor Inhibition 8.0 pKd
staurosporine Hs Inhibitor Inhibition 7.9 pKd
tozasertib Hs Inhibitor Inhibition 7.9 pKd
SU-14813 Hs Inhibitor Inhibition 7.8 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 3,9

Key to terms and symbols Click column headers to sort
Target used in screen: Ret/RET
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
TWS119 Hs Inhibitor Inhibition -0.2 2.0 0.0
GSK-3 inhibitor IX Hs Inhibitor Inhibition 0.1 1.0 0.0
Gö 6976 Hs Inhibitor Inhibition 0.5 -1.0 1.0
staurosporine Hs Inhibitor Inhibition 0.6 3.5 6.0
indirubin derivative E804 Hs Inhibitor Inhibition 1.2 2.0 -1.0
sorafenib Hs Inhibitor Inhibition 1.8
Syk inhibitor Hs Inhibitor Inhibition 1.9 1.0 1.0
K-252a Hs Inhibitor Inhibition 2.4 2.0 1.0
dovitinib Hs Inhibitor Inhibition 2.4
SU11652 Hs Inhibitor Inhibition 2.5 -1.0 -1.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Mrgprdtm1Mjz|Rettm1Ddg|Tg(Wnt1-cre)11Rth Mrgprdtm1Mjz/?,Rettm1Ddg/Rettm1Ddg,Tg(Wnt1-cre)11Rth/0
involves: 129 * 129S1/Sv * C57BL/6 * C57BL/6J * CBA/J
MGI:2447280  MGI:3033142  MGI:97902  MP:0008415 abnormal neurite morphology PMID: 17553423 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Bilateral renal dysplasia
Orphanet: ORPHA93173
Disease:  Central hypoventilation syndrome, congenital; CCHS
Synonyms: Haddad syndrome [Orphanet: ORPHA99803]
Ondine-Hirschsprung disease
OMIM: 209880
Orphanet: ORPHA99803
Disease:  Hirschsprung disease, susceptibility to, 1; HSCR1
Synonyms: Hirschsprung disease [Orphanet: ORPHA388]
OMIM: 142623
Orphanet: ORPHA388
Disease:  Multiple endocrine neoplasia IIA
Synonyms: Multiple endocrine neoplasia [Disease Ontology: DOID:3125]
Disease Ontology: DOID:3125
OMIM: 171400
Orphanet: ORPHA247698
Disease:  Multiple endocrine neoplasia IIB
Synonyms: Multiple endocrine neoplasia [Disease Ontology: DOID:3125]
Disease Ontology: DOID:3125
OMIM: 162300
Orphanet: ORPHA247709
Disease:  Pheochromocytoma
OMIM: 171300
Disease:  Renal agenesis
Disease Ontology: DOID:14766
OMIM: 191830
Orphanet: ORPHA1848
Disease:  Thyroid carcinoma, familial medullary
Synonyms: Familial medullary thyroid carcinoma [Disease Ontology: DOID:0050547]
Disease Ontology: DOID:0050547
OMIM: 155240
Orphanet: ORPHA99361
Disease:  Thyroid carcinoma, papillary
Synonyms: Differentiated thyroid carcinoma [Orphanet: ORPHA146]
Papillary thyroid carcinoma [Disease Ontology: DOID:3969]
Disease Ontology: DOID:3969
OMIM: 188550
Orphanet: ORPHA146
Disease:  Unilateral renal dysplasia
Orphanet: ORPHA93172

References

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1. Akeno-Stuart N, Croyle M, Knauf JA, Malaguarnera R, Vitagliano D, Santoro M, Stephan C, Grosios K, Wartmann M, Cozens R et al.. (2007) The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells. Cancer Res., 67 (14): 6956-64. [PMID:17638907]

2. Albert DH, Tapang P, Magoc TJ, Pease LJ, Reuter DR, Wei RQ, Li J, Guo J, Bousquet PF, Ghoreishi-Haack NS et al.. (2006) Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol. Cancer Ther., 5 (4): 995-1006. [PMID:16648571]

3. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

4. Andrews SW, Aronow S, Blake JF, Brandhuber BJ, Cook A, Hass J, Jiang Y, Kolakowski GR, McFaddin EA, McKenney M et al.. (2018) Substituted pyrazolo[1,5-a]pyridine compounds as ret kinase inhibitors. Patent number: WO2018071447A1. Assignee: Loxo Oncology. Priority date: 10/10/2016. Publication date: 19/04/2018.

5. Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, Ryan AJ, Fontanini G, Fusco A, Santoro M. (2002) ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res., 62 (24): 7284-90. [PMID:12499271]

6. Chao Q, Sprankle KG, Grotzfeld RM, Lai AG, Carter TA, Velasco AM, Gunawardane RN, Cramer MD, Gardner MF, James J et al.. (2009) Identification of N-(5-tert-butyl-isoxazol-3-yl)-N'-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea dihydrochloride (AC220), a uniquely potent, selective, and efficacious FMS-like tyrosine kinase-3 (FLT3) inhibitor. J. Med. Chem., 52 (23): 7808-16. [PMID:19754199]

7. Clemens GR, Schroeder RE, Magness SH, Weaver EV, Lech JW, Taylor VC, Masuda ES, Baluom M, Grossbard EB. (2009) Developmental toxicity associated with receptor tyrosine kinase Ret inhibition in reproductive toxicity testing. Birth Defects Res. Part A Clin. Mol. Teratol., 85 (2): 130-6. [PMID:19107952]

8. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

9. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

10. Huang Z, H. Li H, Zhang Q, Lu F, Hong M, Zhang Z, Guo X, Zhu Y, S. Li S, Liu H. (2017) Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis. ACS Med. Chem. Lett., Articles ASAP.

11. Hudkins RL, Becknell NC, Zulli AL, Underiner TL, Angeles TS, Aimone LD, Albom MS, Chang H, Miknyoczki SJ, Hunter K et al.. (2012) Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5,4-a]pyrrolo[3,4-c]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent. J. Med. Chem., 55 (2): 903-13. [PMID:22148921]

12. Kitagawa D, Yokota K, Gouda M, Narumi Y, Ohmoto H, Nishiwaki E, Akita K, Kirii Y. (2013) Activity-based kinase profiling of approved tyrosine kinase inhibitors. Genes Cells, 18 (2): 110-22. [PMID:23279183]

13. Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, Ibáñez CF, McDonald NQ. (2006) Structure and chemical inhibition of the RET tyrosine kinase domain. J. Biol. Chem., 281 (44): 33577-87. [PMID:16928683]

14. Lee LY, Hernandez D, Rajkhowa T, Smith SC, Raman JR, Nguyen B, Small D, Levis M. (2017) Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood, 129 (2): 257-260. [PMID:27908881]

15. Mologni L, Redaelli S, Morandi A, Plaza-Menacho I, Gambacorti-Passerini C. (2013) Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase. Mol. Cell. Endocrinol., 377 (1-2): 1-6. [PMID:23811235]

16. Mologni L, Rostagno R, Brussolo S, Knowles PP, Kjaer S, Murray-Rust J, Rosso E, Zambon A, Scapozza L, McDonald NQ et al.. (2010) Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors. Bioorg. Med. Chem., 18 (4): 1482-96. [PMID:20117004]

17. Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, Hu W, Cao Q, Sheets MP, Wilson D et al.. (2018) Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov, 8 (7): 836-849. [PMID:29657135]

18. Thomas M, Huang WS, Wen D, Zhu X, Wang Y, Metcalf CA, Liu S, Chen I, Romero J, Zou D et al.. (2011) Discovery of 5-(arenethynyl) hetero-monocyclic derivatives as potent inhibitors of BCR-ABL including the T315I gatekeeper mutant. Bioorg. Med. Chem. Lett., 21 (12): 3743-8. [PMID:21561767]

19. Tian S, Quan H, Xie C, Guo H, Lü F, Xu Y, Li J, Lou L. (2011) YN968D1 is a novel and selective inhibitor of vascular endothelial growth factor receptor-2 tyrosine kinase with potent activity in vitro and in vivo. Cancer Sci., 102 (7): 1374-80. [PMID:21443688]

20. Tovar C, Higgins B, Deo D, Kolinsky K, Liu JJ, Heimbrook DC, Vassilev LT. (2010) Small-molecule inducer of cancer cell polyploidy promotes apoptosis or senescence: Implications for therapy. Cell Cycle, 9 (16): 3364-75. [PMID:20814247]

21. Wang D, Tang F, Wang S, Jiang Z, Zhang L. (2012) Preclinical anti-angiogenesis and anti-tumor activity of SIM010603, an oral, multi-targets receptor tyrosine kinases inhibitor. Cancer Chemother. Pharmacol., 69 (1): 173-83. [PMID:21638122]

22. Wang T, Ioannidis S, Almeida L, Block MH, Davies AM, Lamb ML, Scott DA, Su M, Zhang HJ, Alimzhanov M et al.. (2011) In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors. Bioorg. Med. Chem. Lett., 21 (10): 2958-61. [PMID:21493067]

23. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

24. Zhou Y, Chen Y, Tong L, Xie H, Wen W, Zhang J, Xi Y, Shen Y, Geng M, Wang Y et al.. (2012) AL3810, a multi-tyrosine kinase inhibitor, exhibits potent anti-angiogenic and anti-tumour activity via targeting VEGFR, FGFR and PDGFR. J. Cell. Mol. Med., 16 (10): 2321-30. [PMID:22304225]

How to cite this page

Type XIV RTKs: RET: ret proto-oncogene. Last modified on 12/04/2019. Accessed on 12/12/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2185.