Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLU040A)

• DOT Name: Proto-oncogene tyrosine-protein kinase receptor Ret (RET)
• Synonyms: EC 2.7.10.1; Cadherin family member 12; Proto-oncogene c-Ret
• Gene Name: RET
• Related Disease:
  Multiple endocrine neoplasia type 2A
  Multiple endocrine neoplasia type 2B
  Hirschsprung disease, susceptibility to, 1
  Bilateral renal agenesis
  Familial medullary thyroid carcinoma
  Haddad syndrome
  Hirschsprung disease
  Renal agenesis, unilateral
  Renal hypodysplasia/aplasia 1
• UniProt ID: RET_HUMAN
• PDB ID: 2IVS ; 2IVT ; 2IVU ; 2IVV ; 2X2K ; 2X2L ; 2X2M ; 2X2U ; 4CKI ; 4CKJ ; 4UX8 ; 5AMN ; 5FM2 ; 5FM3 ; 6FEK ; 6GL7 ; 6I82 ; 6I83 ; 6NE7 ; 6NEC ; 6NJA ; 6Q2J ; 6Q2N ; 6Q2O ; 6Q2R ; 6Q2S ; 6VHG ; 7DU8 ; 7DU9 ; 7DUA ; 7JU5 ; 7JU6 ; 7NZN ; 7RUN
• EC Number: 2.7.10.1
• Pfam ID: PF00028 ; PF07714 ; PF17756 ; PF17812 ; PF17813
• Sequence:
  MAKATSGAAGLRLLLLLLLPLLGKVALGLYFSRDAYWEKLYVDQAAGTPLLYVHALRDAP
  EEVPSFRLGQHLYGTYRTRLHENNWICIQEDTGLLYLNRSLDHSSWEKLSVRNRGFPLLT
  VYLKVFLSPTSLREGECQWPGCARVYFSFFNTSFPACSSLKPRELCFPETRPSFRIRENR
  PPGTFHQFRLLPVQFLCPNISVAYRLLEGEGLPFRCAPDSLEVSTRWALDREQREKYELV
  AVCTVHAGAREEVVMVPFPVTVYDEDDSAPTFPAGVDTASAVVEFKRKEDTVVATLRVFD
  ADVVPASGELVRRYTSTLLPGDTWAQQTFRVEHWPNETSVQANGSFVRATVHDYRLVLNR
  NLSISENRTMQLAVLVNDSDFQGPGAGVLLLHFNVSVLPVSLHLPSTYSLSVSRRARRFA
  QIGKVCVENCQAFSGINVQYKLHSSGANCSTLGVVTSAEDTSGILFVNDTKALRRPKCAE
  LHYMVVATDQQTSRQAQAQLLVTVEGSYVAEEAGCPLSCAVSKRRLECEECGGLGSPTGR
  CEWRQGDGKGITRNFSTCSPSTKTCPDGHCDVVETQDINICPQDCLRGSIVGGHEPGEPR
  GIKAGYGTCNCFPEEEKCFCEPEDIQDPLCDELCRTVIAAAVLFSFIVSVLLSAFCIHCY
  HKFAHKPPISSAEMTFRRPAQAFPVSYSSSGARRPSLDSMENQVSVDAFKILEDPKWEFP
  RKNLVLGKTLGEGEFGKVVKATAFHLKGRAGYTTVAVKMLKENASPSELRDLLSEFNVLK
  QVNHPHVIKLYGACSQDGPLLLIVEYAKYGSLRGFLRESRKVGPGYLGSGGSRNSSSLDH
  PDERALTMGDLISFAWQISQGMQYLAEMKLVHRDLAARNILVAEGRKMKISDFGLSRDVY
  EEDSYVKRSQGRIPVKWMAIESLFDHIYTTQSDVWSFGVLLWEIVTLGGNPYPGIPPERL
  FNLLKTGHRMERPDNCSEEMYRLMLQCWKQEPDKRPVFADISKDLEKMMVKRRDYLDLAA
  STPSDSLIYDDGLSEEETPLVDCNNAPLPRALPSTWIENKLYGMSDPNWPGESPVPLTRA
  DGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS
• 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. 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.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Calcium sig.ling pathway (hsa04020)
  PI3K-Akt sig.ling pathway (hsa04151)
  Pathways in cancer (hsa05200)
  Thyroid cancer (hsa05216)
  Non-small cell lung cancer (hsa05223)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  RET signaling (R-HSA-8853659)
  NPAS4 regulates expression of target genes (R-HSA-9768919)
  RAF/MAP kinase cascade (R-HSA-5673001)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple endocrine neoplasia type 2A	DIS7D3W2	Definitive	Autosomal dominant	[1]
Multiple endocrine neoplasia type 2B	DIS6FT6I	Definitive	Autosomal dominant	[1]
Hirschsprung disease, susceptibility to, 1	DISDU2S6	Strong	Autosomal dominant	[2]
Bilateral renal agenesis	DISOR5IA	Supportive	Autosomal recessive	[3]
Familial medullary thyroid carcinoma	DIS01PWX	Supportive	Autosomal dominant	[4]
Haddad syndrome	DISF128S	Supportive	Autosomal dominant	[5]
Hirschsprung disease	DISUUSM1	Supportive	Autosomal dominant	[6]
Renal agenesis, unilateral	DIS53ZJ8	Supportive	Autosomal dominant	[7]
Renal hypodysplasia/aplasia 1	DISOH8XN	Limited	Autosomal recessive	[8]

5 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[9]
Imatinib	DM7RJXL	Approved	Imatinib decreases the phosphorylation of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[22]
Vandetanib	DMRICNP	Approved	Vandetanib decreases the phosphorylation of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[23]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the phosphorylation of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[26]

27 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[11]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[13]
Arsenic	DMTL2Y1	Approved	Arsenic increases the activity of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[16]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[17]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[18]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[18]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[19]
Sulindac	DM2QHZU	Approved	Sulindac affects the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[20]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the activity of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[21]
Estrone	DM5T6US	Approved	Estrone increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[18]
Mestranol	DMG3F94	Approved	Mestranol increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[18]
Meclizine	DMS7T13	Approved	Meclizine affects the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[20]
Methazolamide	DM7J2TA	Approved	Methazolamide affects the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[20]
Megestrol	DMDH9KX	Approved	Megestrol affects the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[24]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[18]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil affects the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[20]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[27]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[30]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[31]
Irbesartan	DMTP1DC	Investigative	Irbesartan increases the expression of Proto-oncogene tyrosine-protein kinase receptor Ret (RET).	[32]

References

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• [3] Renal aplasia in humans is associated with RET mutations. Am J Hum Genet. 2008 Feb;82(2):344-51. doi: 10.1016/j.ajhg.2007.10.008. Epub 2008 Jan 31.
• [4] Mutation analysis reveals novel sequence variants in NTRK1 in sporadic human medullary thyroid carcinoma. J Clin Endocrinol Metab. 1999 Aug;84(8):2784-7. doi: 10.1210/jcem.84.8.5901.
• [5] Point mutation in exon 12 of the receptor tyrosine kinase proto-oncogene RET in Ondine-Hirschsprung syndrome. Pediatrics. 1998 May;101(5):924-6. doi: 10.1542/peds.101.5.924.
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