1. University of Nottingham, UK

Abstract

The RET (REarranged during Transfection) receptor is a transmembrane tyrosine kinase enzyme enzyme. RET forms a complex with members of the GPI-linked GDNF family receptors (GFR) to respond to GDNF family ligands, including glial cell-derived neurotrophic factors including glial cell-derived neurotrophic factor GDNF (211 aa); neurturin (197 aa); artemin (237 aa) and persephin (156 aa). RET also forms a complex with GFRAL, which is activated by growth differentiation factor 15 (GDF15) [25, 35]. RET is involved in neural crest development. Loss of function mutations lead to Hirschprung's disease, while gain of function mutations lead to multiple endocrine neoplasias type 2A and 2B. There are isoforms - RET51 and RET9 - with distinct signalling properties.

Contents

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [5].

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

References

1. Akeno-Stuart N, Croyle M, Knauf JA, Malaguarnera R, Vitagliano D, Santoro M, Stephan C, Grosios K, Wartmann M and 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: 6956-64 [PMID:17638907]
2. Albert DH, Tapang P, Magoc TJ, Pease LJ, Reuter DR, Wei RQ, Li J, Guo J, Bousquet PF and Ghoreishi-Haack NS et al.. (2006) Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor. Mol Cancer Ther 5: 995-1006 [PMID:16648571]
3. Anastassiadis T, Deacon SW, Devarajan K, Ma H and Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol 29: 1039-45 [PMID:22037377]
4. Andrews SW, Aronow S, Blake JF, Brandhuber BJ, Cook A, Hass J, Jiang Y, Kolakowski GR, McFaddin EA and 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. Buneman P, Christie G, Davies JA, Dimitrellou R, Harding SD, Pawson AJ, Sharman JL and Wu Y. (2020) Why data citation isn't working, and what to do about it Database 2020 [PMID:32367113]
6. Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, Ryan AJ, Fontanini G, Fusco A and Santoro M. (2002) ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 62: 7284-90 [PMID:12499271]
7. Chao Q, Sprankle KG, Grotzfeld RM, Lai AG, Carter TA, Velasco AM, Gunawardane RN, Cramer MD, Gardner MF and 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: 7808-16 [PMID:19754199]
8. Chen Z, Duan S, Li G, Han R, Sun Q, Jing L, Han X, Tian Q, Song H and Xue T et al.. (2020) Heterocyclic compound, pharmaceutical composition comprising same, preparation method therefor, and use thereof Patent number: WO2020168939A1. Assignee: Sichuan Kelun Biotech Biopharmaceutical Co. Priority date: 11/02/2020. Publication date: 27/08/2020.
9. Clemens GR, Schroeder RE, Magness SH, Weaver EV, Lech JW, Taylor VC, Masuda ES, Baluom M and 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: 130-6 [PMID:19107952]
10. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK and Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol 29: 1046-51 [PMID:22037378]
11. Drilon A, Oxnard GR, Tan DSW, Loong HHF, Johnson M, Gainor J, McCoach CE, Gautschi O, Besse B and Cho BC et al.. (2020) Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med 383: 813-824 [PMID:32846060]
12. Fabbro D, Cowan-Jacob SW, Möbitz H and Martiny-Baron G. (2012) Targeting cancer with small-molecular-weight kinase inhibitors. Methods Mol Biol 795: 1-34 [PMID:21960212]
13. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R and Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J 451: 313-28 [PMID:23398362]
14. Huang Z, Li H, Zhang Q, Lu F, Hong M, Zhang Z, Guo X, Zhu Y, Li S and Liu H. (2017) Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis. ACS Med Chem Lett 8: 1142-1147 [PMID:29152045]
15. Hudkins RL, Becknell NC, Zulli AL, Underiner TL, Angeles TS, Aimone LD, Albom MS, Chang H, Miknyoczki SJ and 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: 903-13 [PMID:22148921]
16. Inagaki H, Shibata Y, Namiki H, Kageji H, Nakayama K and Kaneta Y. (2018) Pyridine compound Patent number: WO2018060714A1. Assignee: Daiichi Sankyo Company. Priority date: 29/09/2016. Publication date: 05/04/2018.
17. Kitagawa D, Yokota K, Gouda M, Narumi Y, Ohmoto H, Nishiwaki E, Akita K and Kirii Y. (2013) Activity-based kinase profiling of approved tyrosine kinase inhibitors. Genes Cells 18: 110-22 [PMID:23279183]
18. Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, Ibáñez CF and McDonald NQ. (2006) Structure and chemical inhibition of the RET tyrosine kinase domain. J Biol Chem 281: 33577-87 [PMID:16928683]
19. Lee LY, Hernandez D, Rajkhowa T, Smith SC, Raman JR, Nguyen B, Small D and Levis M. (2017) Preclinical studies of gilteritinib, a next-generation FLT3 inhibitor. Blood 129: 257-260 [PMID:27908881]
20. Mathison CJN, Yang Y, Nelson J, Huang Z, Jiang J, Chianelli D, Rucker PV, Roland J, Xie YF and Epple R et al.. (2021) Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-d]pyrimidine RET Inhibitors. ACS Med Chem Lett 12: 1912-1919 [PMID:34917254]
21. Mathison CNJ, Chianelli D, Ruckler PV, Nelson J, Roland J, Huang Z, Yang Y, Jiang J, Xie YF and Epple R et al.. (2020) Efficacy and Tolerability of Pyrazolo[1,5-a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma ACS Med Chem Lett
22. Miyazaki I, Shimamura T, Kato M, Fujita H and Iguchi S. (2018) Novel fused pyrimidine compound or salt thereof Patent number: US20180009818A1. Assignee: Taiho Pharmaceutical Co Ltd. Priority date: 23/01/2016. Publication date: 11/01/2018.
23. Mologni L, Redaelli S, Morandi A, Plaza-Menacho I and Gambacorti-Passerini C. (2013) Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase. Mol Cell Endocrinol 377: 1-6 [PMID:23811235]
24. Mologni L, Rostagno R, Brussolo S, Knowles PP, Kjaer S, Murray-Rust J, Rosso E, Zambon A, Scapozza L and McDonald NQ et al.. (2010) Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors. Bioorg Med Chem 18: 1482-96 [PMID:20117004]
25. Mullican SE, Lin-Schmidt X, Chin CN, Chavez JA, Furman JL, Armstrong AA, Beck SC, South VJ, Dinh TQ and Cash-Mason TD et al.. (2017) GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med 23: 1150-1157 [PMID:28846097]
26. Su Y, Wang J and Bao R. (2020) Inhibitor containing bicyclic derivative, preparation method therefor and use thereof Patent number: WO2020228756A1. Assignee: Shanghai Hansoh Biomedical Technology Co., Ltd., Jiangsu Hansoh Pharmaceutical Group Co., Ltd.. Priority date: 14/05/2020. Publication date: 19/11/2020.
27. Su Y, Wang J and Bao R. (2020) Inhibitor containing bicyclic derivative, preparation method therefor and use thereof Patent number: WO2020228756A1. Assignee: Shanghai Hansoh Biomedical Technology Co., Ltd., Jiangsu Hansoh Pharmaceutical Group Co., Ltd.. Priority date: 14/05/2020. Publication date: 19/11/2020.
28. Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, Hu W, Cao Q, Sheets MP and Wilson D et al.. (2018) Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov 8: 836-849 [PMID:29657135]
29. Thomas M, Huang WS, Wen D, Zhu X, Wang Y, Metcalf CA, Liu S, Chen I, Romero J and 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: 3743-8 [PMID:21561767]
30. Tian S, Quan H, Xie C, Guo H, Lü F, Xu Y, Li J and 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: 1374-80 [PMID:21443688]
31. Tovar C, Higgins B, Deo D, Kolinsky K, Liu JJ, Heimbrook DC and Vassilev LT. (2010) Small-molecule inducer of cancer cell polyploidy promotes apoptosis or senescence: Implications for therapy. Cell Cycle 9: 3364-75 [PMID:20814247]
32. Wang D, Tang F, Wang S, Jiang Z and Zhang L. (2012) Preclinical anti-angiogenesis and anti-tumor activity of SIM010603, an oral, multi-targets receptor tyrosine kinases inhibitor. Cancer Chemother Pharmacol 69: 173-83 [PMID:21638122]
33. Wang T, Ioannidis S, Almeida L, Block MH, Davies AM, Lamb ML, Scott DA, Su M, Zhang HJ and 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: 2958-61 [PMID:21493067]
34. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC and Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol 17: 1241-9 [PMID:21095574]
35. Yang L, Chang CC, Sun Z, Madsen D, Zhu H, Padkjær SB, Wu X, Huang T, Hultman K and Paulsen SJ et al.. (2017) GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med 23: 1158-1166 [PMID:28846099]
36. Zhong J, Xue W, Gao Q, Liu Y, Chen X, Xie W, Xiao R, Hao Y, Lin Y and Chen L et al.. (2025) Discovery of APS03118, a Potent and Selective Next-Generation RET Inhibitor with a Novel Kinase Hinge Scaffold. J Med Chem [PMID:40920215]
37. Zhou Y, Chen Y, Tong L, Xie H, Wen W, Zhang J, Xi Y, Shen Y, Geng M and 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: 2321-30 [PMID:22304225]