Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT4DXQT)

• DTT Name: Proto-oncogene c-Ret (RET)
• 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
• Gene Name: RET
• DTT Type: Successful target; [1]
• Related Disease:
  Colorectal cancer [ICD-11: 2B91]
  Lung cancer [ICD-11: 2C25]
  Mature B-cell lymphoma [ICD-11: 2A85]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]
  Thrombocytopenia [ICD-11: 3B64]
  Thyroid cancer [ICD-11: 2D10]
• BioChemical Class: Kinase
• UniProt ID: RET_HUMAN
• TTD ID: T60631
• 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
• 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.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Pathways in cancer (hsa05200)
  Thyroid cancer (hsa05216)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  RET signaling (R-HSA-8853659)
  RAF/MAP kinase cascade (R-HSA-5673001)

Molecular Interaction Atlas (MIA) of This DTT

6 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ponatinib	DMYGJQO	Acute lymphoblastic leukaemia	2A85	Approved	[2]
Pralsetinib	DMWU0I2	Non-small-cell lung cancer	2C25.Y	Approved	[3]
Regorafenib	DMHSY1I	Metastatic colorectal cancer	2B91	Approved	[2]
Romiplostim	DM3U7SZ	Thrombocytopenia	3B64	Approved	[1]
Selpercatinib	DMZR15V	Non-small-cell lung cancer	2C25.Y	Approved	[4]
Vandetanib	DMRICNP	Solid tumour/cancer	2A00-2F9Z	Approved	[5], [6]

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MGCD516	DM752PU	Solid tumour/cancer	2A00-2F9Z	Phase 2/3	[7]
MGCD516	DM752PU	Solid tumour/cancer	2A00-2F9Z	Phase 2/3	[8]
CEP-32496	DMAO04B	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[9]
TPX-0046	DMIVE67	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[10]
BOS172738	DM9L0D8	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
GSK3179106	DM2KCIP	Inflammatory bowel disease	DD72	Phase 1	[12]
tamatinib	DMGANIC	Solid tumour/cancer	2A00-2F9Z	Clinical trial	[13]

30 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Benzo(b)carbazol-11-one compound 1	DM4VXY1	N. A.	N. A.	Patented	[14]
Benzo(b)carbazol-11-one compound 2	DMGCHW9	N. A.	N. A.	Patented	[14]
Carboxamide derivative 4	DMU5GKC	N. A.	N. A.	Patented	[14]
Dihydropyridine compound 1	DM16M4A	N. A.	N. A.	Patented	[14]
Dihydropyridine compound 2	DM6RGOY	N. A.	N. A.	Patented	[14]
Dihydropyridine compound 3	DMR3AVK	N. A.	N. A.	Patented	[14]
Dihydropyridine compound 4	DMIFZLG	N. A.	N. A.	Patented	[14]
Dihydropyridine compound 5	DMC41TK	N. A.	N. A.	Patented	[14]
Dihydropyridine compound 6	DMEXT6J	N. A.	N. A.	Patented	[14]
Pyrazolo[3,4-d]pyrimidine derivative 5	DMIH0F4	N. A.	N. A.	Patented	[14]
Pyrazolo[3,4-d]pyrimidine derivative 6	DMCTWVY	N. A.	N. A.	Patented	[14]
Pyrazolo[3,4-d]pyrimidine derivative 7	DM4GF58	N. A.	N. A.	Patented	[14]
Pyrazolo[3,4-d]pyrimidine derivative 8	DM89GKE	N. A.	N. A.	Patented	[14]
Pyridine derivative 18	DMBZMYT	N. A.	N. A.	Patented	[14]
Pyridine derivative 19	DMXYT40	N. A.	N. A.	Patented	[14]
Pyridine derivative 20	DMAOF0W	N. A.	N. A.	Patented	[14]
Pyridine derivative 21	DMF3907	N. A.	N. A.	Patented	[14]
Pyridine derivative 22	DMSIERF	N. A.	N. A.	Patented	[14]
Pyrrolo-pyridinone derivative 1	DMK820T	N. A.	N. A.	Patented	[14]
Pyrrolo-pyridinone derivative 2	DM5G67X	N. A.	N. A.	Patented	[14]
Pyrrolo-pyridinone derivative 3	DME1Q3W	N. A.	N. A.	Patented	[14]
Pyrrolo-pyridinone derivative 4	DM2EVJR	N. A.	N. A.	Patented	[14]
Pyrrolo-pyrimidine derivative 2	DMEHYBJ	N. A.	N. A.	Patented	[14]
Pyrrolo-pyrimidine derivative 3	DMKHWN9	N. A.	N. A.	Patented	[14]
Pyrrolo-pyrimidine derivative 4	DMITK03	N. A.	N. A.	Patented	[14]
Pyrrolo-pyrimidine derivative 5	DMVA95G	N. A.	N. A.	Patented	[14]
Pyrrolo-pyrimidine derivative 6	DMGYT81	N. A.	N. A.	Patented	[14]
Quinazoline derivative 14	DMHLJA7	N. A.	N. A.	Patented	[14]
Quinazoline derivative 15	DMD965S	N. A.	N. A.	Patented	[14]
Quinazoline derivative 16	DMQ704Z	N. A.	N. A.	Patented	[14]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CEP-751	DM956N7	Neurodegenerative disorder	8A20-8A23	Terminated	[15]

9 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(E)-3-(4-hydroxybenzylidene)indolin-2-one	DMX4U9L	Discovery agent	N.A.	Investigative	[1]
(Z)-3-((1H-pyrrol-2-yl)methylene)indolin-2-one	DM27WDP	Discovery agent	N.A.	Investigative	[1]
(Z)-5-Amino-3-(4-methoxybenzylidene)indolin-2-one	DMPJAKL	Discovery agent	N.A.	Investigative	[1]
AST-487	DME76KU	Discovery agent	N.A.	Investigative	[16]
GW-559768X	DMGRKT4	Solid tumour/cancer	2A00-2F9Z	Investigative	[7]
ITRI-305	DMWTDS8	Thyroid cancer	2D10	Investigative	[7]
PMID21493067C1d	DMFUQIT	Discovery agent	N.A.	Investigative	[17]
PMID21561767C8h	DMABZH6	Discovery agent	N.A.	Investigative	[18]
TG-100435	DMIR3X2	Discovery agent	N.A.	Investigative	[19]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rectal cancer	2C82	Rectal colon tissue	3.48E-02	-0.23	-1.17
Myelodysplastic syndrome	2C82	Bone marrow	2.22E-01	1.05E-02	0.03
Thyroid cancer	2C82	Thyroid	1.04E-09	0.09	0.23
Renal cancer	2C82	Kidney	2.51E-02	-0.24	-0.46
Gastric cancer	2C82	Gastric tissue	4.93E-01	-0.48	-1.16
Ovarian cancer	2C82	Ovarian tissue	2.42E-01	-0.03	-0.11
Lung cancer	2C82	Lung tissue	3.31E-11	0.03	0.11
Breast cancer	2C82	Breast tissue	5.81E-76	0.64	1.56
Acute myelocytic leukaemia	2C82	Bone marrow	5.83E-05	0.15	0.5
Lateral sclerosis	8A00.0	Cervical spinal cord	9.18E-01	-0.36	-0.48
Head and neck cancer	2C82	Head and neck tissue	2.64E-03	0.05	0.19

References

• [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.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [5] 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.
• [6] Clinical pipeline report, company report or official report of AstraZeneca (2009).
• [7] 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).
• [8] Role and relevance of TrkB mutations and expression in non-small cell lung cancer. Clin Cancer Res. 2011 May 1;17(9):2638-45.
• [9] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [10] Clinical pipeline report, company report or official report of Turning Point Therapeutics.
• [11] National Cancer Institute Drug Dictionary (drug name Zeteletinib).
• [12] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [13] 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.
• [14] RET kinase inhibitors: a review of recent patents (2012-2015).Expert Opin Ther Pat. 2017 Jan;27(1):91-99.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.