Details of Drug Off-Target (DOT)

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

• DOT Name: High affinity nerve growth factor receptor (NTRK1)
• Synonyms: EC 2.7.10.1; Neurotrophic tyrosine kinase receptor type 1; TRK1-transforming tyrosine kinase protein; Tropomyosin-related kinase A; Tyrosine kinase receptor; Tyrosine kinase receptor A; Trk-A; gp140trk; p140-TrkA
• Gene Name: NTRK1
• Related Disease:
  Hereditary sensory and autonomic neuropathy type 4
  Familial medullary thyroid carcinoma
• UniProt ID: NTRK1_HUMAN
• PDB ID: 1HE7 ; 1SHC ; 1WWA ; 1WWW ; 2IFG ; 2N90 ; 4AOJ ; 4CRP ; 4F0I ; 4GT5 ; 4PMM ; 4PMP ; 4PMS ; 4PMT ; 4YNE ; 4YPS ; 5H3Q ; 5I8A ; 5JFS ; 5JFV ; 5JFW ; 5JFX ; 5KMI ; 5KMJ ; 5KMK ; 5KML ; 5KMM ; 5KMN ; 5KMO ; 5KVT ; 5WR7 ; 6D1Y ; 6D1Z ; 6D20 ; 6D22 ; 6DKB ; 6DKG ; 6DKI ; 6DKW ; 6IQN ; 6J5L ; 6NPT ; 6NSP ; 6NSS ; 6PL1 ; 6PL2 ; 6PL3 ; 6PL4 ; 6PMA ; 6PMB ; 6PMC ; 6PME ; 7N3T ; 7VKM ; 7VKN ; 7VKO ; 7XAF ; 7XBI ; 8J5W ; 8J5X ; 8J61 ; 8J63
• EC Number: 2.7.10.1
• Pfam ID: PF13855 ; PF16920 ; PF07714 ; PF18613
• Sequence:
  MLRGGRRGQLGWHSWAAGPGSLLAWLILASAGAAPCPDACCPHGSSGLRCTRDGALDSLH
  HLPGAENLTELYIENQQHLQHLELRDLRGLGELRNLTIVKSGLRFVAPDAFHFTPRLSRL
  NLSFNALESLSWKTVQGLSLQELVLSGNPLHCSCALRWLQRWEEEGLGGVPEQKLQCHGQ
  GPLAHMPNASCGVPTLKVQVPNASVDVGDDVLLRCQVEGRGLEQAGWILTELEQSATVMK
  SGGLPSLGLTLANVTSDLNRKNVTCWAENDVGRAEVSVQVNVSFPASVQLHTAVEMHHWC
  IPFSVDGQPAPSLRWLFNGSVLNETSFIFTEFLEPAANETVRHGCLRLNQPTHVNNGNYT
  LLAANPFGQASASIMAAFMDNPFEFNPEDPIPVSFSPVDTNSTSGDPVEKKDETPFGVSV
  AVGLAVFACLFLSTLLLVLNKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTE
  GKGSGLQGHIIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKML
  VAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVFEYMRHGDLNRF
  LRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMVYLAGLHFVHRDLATRNCLVGQ
  GLVVKIGDFGMSRDIYSTDYYRVGGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEI
  FTYGKQPWYQLSNTEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHAR
  LQALAQAPPVYLDVLG
• Function: Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand. Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors; [Isoform TrkA-III]: Resistant to NGF, it constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.
• Tissue Specificity: Isoform TrkA-I is found in most non-neuronal tissues. Isoform TrkA-II is primarily expressed in neuronal cells. TrkA-III is specifically expressed by pluripotent neural stem and neural crest progenitors.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Calcium sig.ling pathway (hsa04020)
  PI3K-Akt sig.ling pathway (hsa04151)
  Apoptosis (hsa04210)
  Neurotrophin sig.ling pathway (hsa04722)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Thyroid cancer (hsa05216)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  Signalling to RAS (R-HSA-167044)
  ARMS-mediated activation (R-HSA-170984)
  Retrograde neurotrophin signalling (R-HSA-177504)
  NGF-independant TRKA activation (R-HSA-187024)
  TRKA activation by NGF (R-HSA-187042)
  Signalling to p38 via RIT and RIN (R-HSA-187706)
  PI3K/AKT activation (R-HSA-198203)
  Signalling to STAT3 (R-HSA-198745)
  PLC-gamma1 signalling (R-HSA-167021)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hereditary sensory and autonomic neuropathy type 4	DISNE3R5	Definitive	Autosomal recessive	[1]
Familial medullary thyroid carcinoma	DIS01PWX	Supportive	Autosomal dominant	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of High affinity nerve growth factor receptor (NTRK1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of High affinity nerve growth factor receptor (NTRK1).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of High affinity nerve growth factor receptor (NTRK1).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of High affinity nerve growth factor receptor (NTRK1).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of High affinity nerve growth factor receptor (NTRK1).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of High affinity nerve growth factor receptor (NTRK1).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of High affinity nerve growth factor receptor (NTRK1).	[10]
Marinol	DM70IK5	Approved	Marinol decreases the expression of High affinity nerve growth factor receptor (NTRK1).	[11]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of High affinity nerve growth factor receptor (NTRK1).	[13]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of High affinity nerve growth factor receptor (NTRK1).	[14]
GDC0941	DM1YAK6	Phase 2	GDC0941 decreases the activity of High affinity nerve growth factor receptor (NTRK1).	[15]
MK-2461	DM21WBH	Phase 1/2	MK-2461 decreases the activity of High affinity nerve growth factor receptor (NTRK1).	[16]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of High affinity nerve growth factor receptor (NTRK1).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of High affinity nerve growth factor receptor (NTRK1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of High affinity nerve growth factor receptor (NTRK1).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of High affinity nerve growth factor receptor (NTRK1).	[21]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of High affinity nerve growth factor receptor (NTRK1).	[22]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of High affinity nerve growth factor receptor (NTRK1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of High affinity nerve growth factor receptor (NTRK1).	[6]
Menadione	DMSJDTY	Approved	Menadione increases the phosphorylation of High affinity nerve growth factor receptor (NTRK1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of High affinity nerve growth factor receptor (NTRK1).	[17]

References

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• [2] 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.
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• [7] Arsenic trioxide induces cell cycle arrest and affects Trk receptor expression in human neuroblastoma SK-N-SH cells. Biol Res. 2018 Jun 13;51(1):18. doi: 10.1186/s40659-018-0167-6.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] Effect of cell differentiation for neuroblastoma by vitamin k analogs. Jpn J Clin Oncol. 2009 Apr;39(4):251-9. doi: 10.1093/jjco/hyp011. Epub 2009 Mar 8.
• [13] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [14] Long term effects of cigarette smoke extract or nicotine on nerve growth factor and its receptors in a bronchial epithelial cell line. Toxicol In Vitro. 2018 Dec;53:29-36. doi: 10.1016/j.tiv.2018.07.020. Epub 2018 Aug 1.
• [15] The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem. 2008 Sep 25;51(18):5522-32. doi: 10.1021/jm800295d.
• [16] Discovery of a 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (MK-2461) inhibitor of c-Met kinase for the treatment of cancer. J Med Chem. 2011 Jun 23;54(12):4092-108. doi: 10.1021/jm200112k. Epub 2011 May 24.
• [17] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [18] AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
• [19] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Anticarcinogenic activities of sulforaphane are influenced by Nerve Growth Factor in human melanoma A375 cells. Food Chem Toxicol. 2018 Mar;113:154-161. doi: 10.1016/j.fct.2018.01.051. Epub 2018 Jan 31.
• [22] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [23] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.