Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Tropomyosin-related kinase A (TrkA)
• Synonyms: gp140trk; Tyrosine kinase receptor A; Tyrosine kinase receptor; Trk-A; TRKA; TRK1-transforming tyrosine kinase protein; TRK1 transforming tyrosinekinase protein; TRK; P140-TrkA; Neurotrophic tyrosine kinase receptor type 1; NGF-trk receptor type A; MTC; High affinity nerve growth factor receptor
• Gene Name: NTRK1
• DTT Type: Successful target; [1]
• Related Disease:
  Non-small cell lung cancer [ICD-11: 2C25]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• BioChemical Class: Kinase
• UniProt ID: NTRK1_HUMAN
• TTD ID: T07173
• EC Number: EC 2.7.10.1
• Sequence:
  MLRGGRRGQLGWHSWAAGPGSLLAWLILASAGAAPCPDACCPHGSSGLRCTRDGALDSLH
  HLPGAENLTELYIENQQHLQHLELRDLRGLGELRNLTIVKSGLRFVAPDAFHFTPRLSRL
  NLSFNALESLSWKTVQGLSLQELVLSGNPLHCSCALRWLQRWEEEGLGGVPEQKLQCHGQ
  GPLAHMPNASCGVPTLKVQVPNASVDVGDDVLLRCQVEGRGLEQAGWILTELEQSATVMK
  SGGLPSLGLTLANVTSDLNRKNVTCWAENDVGRAEVSVQVNVSFPASVQLHTAVEMHHWC
  IPFSVDGQPAPSLRWLFNGSVLNETSFIFTEFLEPAANETVRHGCLRLNQPTHVNNGNYT
  LLAANPFGQASASIMAAFMDNPFEFNPEDPIPVSFSPVDTNSTSGDPVEKKDETPFGVSV
  AVGLAVFACLFLSTLLLVLNKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTE
  GKGSGLQGHIIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKML
  VAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVFEYMRHGDLNRF
  LRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMVYLAGLHFVHRDLATRNCLVGQ
  GLVVKIGDFGMSRDIYSTDYYRVGGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEI
  FTYGKQPWYQLSNTEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHAR
  LQALAQAPPVYLDVLG
• Function: 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. 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.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  Endocytosis (hsa04144)
  Apoptosis (hsa04210)
  Neurotrophin signaling pathway (hsa04722)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Thyroid cancer (hsa05216)
  Central carbon metabolism in cancer (hsa05230)
• Reactome Pathway:
  ARMS-mediated activation (R-HSA-170984)
  NGF-independant TRKA activation (R-HSA-187024)
  PI3K/AKT activation (R-HSA-198203)
  Frs2-mediated activation (R-HSA-170968)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Entrectinib	DMMPTLH	Non-small cell lung cancer	2C25	Approved	[2]
Larotrectinib	DM26CQR	Solid tumour/cancer	2A00-2F9Z	Approved	[1], [3]

10 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MIM-D3	DMZHN5B	Alzheimer disease	8A20	Phase 3	[4]
CT 327	DMQXL1T	Plaque psoriasis	EA90.0	Phase 2	[5]
SNA-120	DMPN314	Plaque psoriasis	EA90.0	Phase 2	[6]
ONO-7579	DMXLPYE	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[7]
TPX-0005	DM9FB2T	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[7]
Altiratinib	DMUJCBT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
DS-6051	DM0RD4F	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
LOXO-195	DMDXFBJ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
PLX7486	DM0IVGU	Pancreatic cancer	2C10	Phase 1	[10], [7]
VMD-928	DM4AXPT	Lymphoma	2A80-2A86	Phase 1	[11]

121 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
3-amino-5-benzyl-substituted indazole derivative 1	DMFDURZ	Chronic pain	MG30	Patented	[12]
Azaindazole amide derivative 1	DMJWH4B	Chronic pain	MG30	Patented	[12]
Benzimidazole derivative 6	DMV7TMB	Solid tumour/cancer	2A00-2F9Z	Patented	[8]
Bicyclic heteroaryl benzamide derivative 1	DMTBWC9	Chronic pain	MG30	Patented	[12]
Bicyclic heteroaryl benzamide derivative 2	DM5MT4R	Chronic pain	MG30	Patented	[12]
Bicyclic heteroaryl benzamide derivative 3	DM54EV2	Chronic pain	MG30	Patented	[12]
Bicyclic heteroaryl benzamide derivative 4	DMUBDYG	Chronic pain	MG30	Patented	[12]
Bicyclic heteroaryl benzamide derivative 5	DMFOVPT	Chronic pain	MG30	Patented	[12]
Bicyclic heteroaryl benzamide derivative 6	DMQGYWV	Chronic pain	MG30	Patented	[12]
Bicyclic heteroaryl benzamide derivative 7	DMM1LKF	Chronic pain	MG30	Patented	[12]
Bicyclic heteroaryl benzamide derivative 8	DMVBQJ1	Chronic pain	MG30	Patented	[12]
Bicyclic heteroaryl benzamide derivative 9	DMGONY4	Chronic pain	MG30	Patented	[12]
Five membered heterocyclic benzamide derivative 1	DMPFAST	Chronic pain	MG30	Patented	[12]
Five membered heterocyclic benzamide derivative 2	DM4U63E	Chronic pain	MG30	Patented	[12]
Five membered heterocyclic benzamide derivative 3	DMUS4Z0	Chronic pain	MG30	Patented	[12]
Imidazo pyridine derivative 1	DMCXHGW	Chronic pain	MG30	Patented	[12]
Imidazo[1,2-b]pyridazine derivative 1	DMULTAI	Solid tumour/cancer	2A00-2F9Z	Patented	[8]
Imidazo[1,2-b]pyridazine derivative 2	DM1JYNW	Solid tumour/cancer	2A00-2F9Z	Patented	[8]
Imidazo[1,2-b]pyridazine derivative 3	DMPDTG0	Solid tumour/cancer	2A00-2F9Z	Patented	[8]
Imidazo[1,2-b]pyridazine derivative 4	DM2DL4I	N. A.	N. A.	Patented	[8]
Imidazo[1,2-b]pyridazine derivative 5	DMK8V7A	N. A.	N. A.	Patented	[8]
Imidazo[1,2-b]pyridazine derivative 6	DMSIRC2	N. A.	N. A.	Patented	[8]
Imidazo[1,2-b]pyridazine derivative 7	DMDQLUP	N. A.	N. A.	Patented	[8]
N,N-bis(5-pyrazoyl)urea derivative 1	DMSD4G0	N. A.	N. A.	Patented	[8]
N-(phenylpyrazolyl)benzamide derivative 1	DM0ZJX7	Chronic pain	MG30	Patented	[12]
N-acylpiperidine ether derivative 1	DM5GCUR	Chronic pain	MG30	Patented	[12]
N-acylpiperidine ether derivative 2	DM02RQ4	Chronic pain	MG30	Patented	[12]
N-acylpiperidine ether derivative 3	DMXWE5R	Chronic pain	MG30	Patented	[12]
N-acylpiperidine ether derivative 4	DMBUQDR	Chronic pain	MG30	Patented	[12]
N-acylpiperidine ether derivative 5	DMQ2MKT	Chronic pain	MG30	Patented	[12]
N-acylpiperidine ether derivative 6	DMAS01P	Chronic pain	MG30	Patented	[12]
N-acylpiperidine ether derivative 7	DMCJR4N	Chronic pain	MG30	Patented	[12]
N-acylpyrrolidine ether derivative 1	DMQ4ULC	Chronic pain	MG30	Patented	[12]
N-acylpyrrolidine ether derivative 2	DMK4Y71	Chronic pain	MG30	Patented	[12]
N-arylmethyl-N-phenyl cyclic urea derivative 1	DMQHAU1	N. A.	N. A.	Patented	[8]
N-arylmethyl-N-phenyl cyclic urea derivative 2	DMWVQDA	N. A.	N. A.	Patented	[8]
PMID28270010-Compound-Figure16-a	DMBHRUP	N. A.	N. A.	Patented	[8]
PMID28270010-Compound-Figure16-b-1	DMAIRL2	N. A.	N. A.	Patented	[8]
PMID28270010-Compound-Figure16-b-2	DM6YLMB	N. A.	N. A.	Patented	[8]
PMID28270010-Compound-Figure17-1	DMPOI27	N. A.	N. A.	Patented	[8]
PMID28270010-Compound-Figure17-2	DM7QLX8	N. A.	N. A.	Patented	[8]
PMID28270010-Compound-Figure17-3	DME0TUJ	N. A.	N. A.	Patented	[8]
PMID28270010-Compound-Figure24-a	DMNTQL5	N. A.	N. A.	Patented	[8]
PMID28270010-Compound-Figure24-b	DM0QHLK	N. A.	N. A.	Patented	[8]
PMID28270010-Compound-Figure5-1	DM2YAPJ	N. A.	N. A.	Patented	[8]
PMID28270010-Compound-Figure5-2	DMK3GRZ	N. A.	N. A.	Patented	[8]
PMID28270010-Compound-Figure5-3	DMSOT1R	N. A.	N. A.	Patented	[8]
PMID28270021-Compound-WO2010077680 103	DM437ZC	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2010077680 109	DMNUA21	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2010077680 201	DMQAZMC	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2010077680 481	DM6VAS2	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2010077680 495	DMQ9CBS	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2010077680 803	DM6TJU0	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2010077680 811	DM47FNS	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2013009582Example16	DMVS7CJ	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2013009582Example76	DMQK4IX	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2013161919Example85-117	DM2XKTB	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2014078408Example1	DMO02EL	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2014078408Example26	DMVCBSK	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2014129431Example8-1	DMKO4ZH	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2014152663 701	DMA04P6	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2015042088Example11	DM16URY	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2015042088Example12	DMOZHGU	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2015042088Example4	DM6KXOQ	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2016054807Example1	DMD5QEL	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2016054807Example112	DMW2ZRM	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2016054807Example71	DMREZ9I	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2016054807Example80	DMPI86D	Chronic pain	MG30	Patented	[12]
PMID28270021-Compound-WO2016054807Example82	DM9ADSN	Chronic pain	MG30	Patented	[12]
Pyrazolo[1,5-a]pyridine derivative 1	DMH1W89	Chronic pain	MG30	Patented	[12]
Pyrazolo[1,5-a]pyridine derivative 2	DMLS827	Chronic pain	MG30	Patented	[12]
Pyrazolo[1,5-a]pyrimidine derivative 14	DMB6EFV	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 15	DMAZI3D	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 16	DMTYN2D	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 17	DMNIER3	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 18	DMVEP6Y	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 19	DMFV36A	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 20	DMJLU8R	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 21	DMWNZTI	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 22	DMG5CXB	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 23	DMQVLP8	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 24	DMT4ZP9	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 25	DMKE7YO	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 26	DMGZ59Q	N. A.	N. A.	Patented	[8]
Pyrazolo[1,5-a]pyrimidine derivative 27	DM9OXAB	N. A.	N. A.	Patented	[8]
Pyrazolo[4,3-c]pyridine derivative 1	DMHRUIZ	Chronic pain	MG30	Patented	[12]
Pyrazolo[4,3-h]quinazoline-3-carboxamide derivative 1	DMTM82B	Chronic pain	MG30	Patented	[12]
Pyrido[3,2-d]pyrimidine derivative 2	DMRHAU4	Chronic pain	MG30	Patented	[12]
Pyrido[3,2-d]pyrimidine derivative 3	DM6D1XR	Chronic pain	MG30	Patented	[12]
Pyrrolidinyl urea derivative 10	DMV6YXJ	N. A.	N. A.	Patented	[8]
Pyrrolidinyl urea derivative 11	DMWKSF3	N. A.	N. A.	Patented	[8]
Pyrrolidinyl urea derivative 12	DMJ6IE5	N. A.	N. A.	Patented	[8]
Pyrrolidinyl urea derivative 13	DM3VL82	N. A.	N. A.	Patented	[8]
Pyrrolidinyl urea derivative 2	DMYFP95	N. A.	N. A.	Patented	[8]
Pyrrolidinyl urea derivative 3	DMFDLHN	N. A.	N. A.	Patented	[8]
Pyrrolidinyl urea derivative 4	DM8SZKU	N. A.	N. A.	Patented	[8]
Pyrrolidinyl urea derivative 5	DMU51T4	N. A.	N. A.	Patented	[8]
Pyrrolidinyl urea derivative 6	DM01GEB	N. A.	N. A.	Patented	[8]
Pyrrolidinyl urea derivative 7	DMYADJP	N. A.	N. A.	Patented	[8]
Pyrrolidinyl urea derivative 8	DMW2JG8	N. A.	N. A.	Patented	[8]
Pyrrolidinyl urea derivative 9	DMO1I4W	N. A.	N. A.	Patented	[8]
Pyrrolo[2,3-b]pyridine derivative 1	DMVKCQU	Chronic pain	MG30	Patented	[12]
Pyrrolo[2,3-b]pyridine derivative 2	DM7IPWB	Chronic pain	MG30	Patented	[12]
Pyrrolo[2,3-b]pyridine derivative 3	DMCYOL7	Chronic pain	MG30	Patented	[12]
Pyrrolo[2,3-d]pyrimidine derivative 3	DMTX1G4	Chronic pain	MG30	Patented	[12]
Pyrrolo[2,3-d]pyrimidine derivative 4	DME0WSR	Chronic pain	MG30	Patented	[12]
Pyrrolo[3,2-c]pyridine derivative 1	DMKF8HI	Chronic pain	MG30	Patented	[12]
Six-membered heterocyclic benzamide derivative 1	DMYFK85	Chronic pain	MG30	Patented	[12]
Six-membered heterocyclic benzamide derivative 2	DMX6AKV	Chronic pain	MG30	Patented	[12]
Six-membered heterocyclic benzamide derivative 3	DMEGVD4	Chronic pain	MG30	Patented	[12]
Six-membered heterocyclic benzamide derivative 4	DMB0D1H	Chronic pain	MG30	Patented	[12]
Six-membered heterocyclic benzamide derivative 5	DM0GTUH	Chronic pain	MG30	Patented	[12]
Six-membered heterocyclic benzamide derivative 6	DMZU96C	Chronic pain	MG30	Patented	[12]
Six-membered heterocyclic benzamide derivative 7	DM15AFI	Chronic pain	MG30	Patented	[12]
Thiadiazolyl carboxamide derivative 1	DMX93AI	Alzheimer disease	8A20	Patented	[8]
Thiazole derivative 4	DM5UQK6	N. A.	N. A.	Patented	[8]
Tri-substituted urea derivative 1	DMHGRTX	Chronic pain	MG30	Patented	[12]
Tri-substituted urea derivative 2	DMUVPR8	Chronic pain	MG30	Patented	[12]
Triazolo[4,3-b]pyridazine derivative 2	DMMJ1FN	Chronic pain	MG30	Patented	[12]
Ureido-phenyl-substituted triazine derivative 1	DMN51XF	N. A.	N. A.	Patented	[8]
Ureido-phenyl-substituted triazine derivative 2	DMR0JDW	N. A.	N. A.	Patented	[8]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AZD6918	DM2QHVW	Advanced solid tumour	2A00-2F9Z	Discontinued in Phase 1	[13]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
FX-007	DMXE6ML	Pain	MG30-MG3Z	Preclinical	[14]

4 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CEP-5104	DMV43GY	Discovery agent	N.A.	Investigative	[15]
CEP-6331	DMNXBTD	Discovery agent	N.A.	Investigative	[15]
GW-5074	DMIHOYF	Discovery agent	N.A.	Investigative	[16]
K-252a analogue	DMCZPH4	Discovery agent	N.A.	Investigative	[17]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Psoriasis	EA90	Skin	4.28E-01	-0.13	-0.27
Alzheimer's disease	8A00.0	Entorhinal cortex	8.72E-01	-0.04	-0.22

References

• [1] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2019
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye. Clin Ophthalmol. 2013; 7: 1275-1285.
• [5] Topical TrkA Kinase Inhibitor CT327 is an Effective, Novel Therapy for the Treatment of Pruritus due to Psoriasis: Results from Experimental Studies, and Efficacy and Safety of CT327 in a Phase 2b Clinical Trial in Patients with Psoriasis. Acta Derm Venereol. 2015 May;95(5):542-8.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part I.Expert Opin Ther Pat. 2017 Jun;27(6):733-751.
• [9] National Cancer Institute Drug Dictionary (drug id 766123).
• [10] National Cancer Institute Drug Dictionary (drug id 747694).
• [11] ClinicalTrials.gov (NCT03556228) Oral TrkA Inhibitor VMD-928 for Treatment of Advanced Adult Solid Tumors or Lymphoma. U.S. National Institutes of Health.
• [12] Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Part II.Expert Opin Ther Pat. 2017 Jul;27(7):831-849.
• [13] Clinical pipeline report, company report or official report of AstraZeneca (2009).
• [14] Preclinical trail of FX007 for treating osteoarthritis. Flexion Therapeutics Inc.
• [15] Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthyl[3,4-a]pyrrolo[3,4-c]carbazole-5-ones: optimization, mixed-linea... J Med Chem. 2008 Sep 25;51(18):5680-9.
• [16] Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles. Bioorg Med Chem Lett. 2004 Feb 23;14(4):953-7.
• [17] Synthesis, modeling, and in vitro activity of (3'S)-epi-K-252a analogues. Elucidating the stereochemical requirements of the 3'-sugar alcohol on tr... J Med Chem. 2005 Jun 2;48(11):3776-83.