| Structural highlights
Disease
[NTRK1_HUMAN] Defects in NTRK1 are a cause of congenital insensitivity to pain with anhidrosis (CIPA) [MIM:256800]. CIPA is characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] Defects in NTRK1 are a cause of thyroid papillary carcinoma (TPC) [MIM:188550]. TPC is a common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=Chromosomal aberrations involving NTRK1 are found in thyroid papillary carcinomas. Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1; a rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1; an intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein.
Function
[NTRK1_HUMAN] 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, it 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.[11] [12] [13] [14] [15] [16] Isoform TrkA-III is resistant to NGF, 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.[17] [18] [19] [20] [21] [22]
Publication Abstract from PubMed
We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitors series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.
Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain.,Stachel SJ, Sanders JM, Henze DA, Rudd MT, Su HP, Li Y, Nanda KK, Egbertson MS, Manley PJ, Jones KL, Brnardic EJ, Green A, Grobler JA, Hanney B, Leitl M, Lai MT, Munshi V, Murphy D, Rickert K, Riley D, Krasowska-Zoladek A, Daley C, Zuck P, Kane SA, Bilodeau M J Med Chem. 2014 Jun 10. PMID:24914455[23]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Indo Y, Tsuruta M, Hayashida Y, Karim MA, Ohta K, Kawano T, Mitsubuchi H, Tonoki H, Awaya Y, Matsuda I. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Nat Genet. 1996 Aug;13(4):485-8. PMID:8696348 doi:10.1038/ng0896-485
- ↑ Greco A, Villa R, Tubino B, Romano L, Penso D, Pierotti MA. A novel NTRK1 mutation associated with congenital insensitivity to pain with anhidrosis. Am J Hum Genet. 1999 Apr;64(4):1207-10. PMID:10090906
- ↑ Mardy S, Miura Y, Endo F, Matsuda I, Sztriha L, Frossard P, Moosa A, Ismail EA, Macaya A, Andria G, Toscano E, Gibson W, Graham GE, Indo Y. Congenital insensitivity to pain with anhidrosis: novel mutations in the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor. Am J Hum Genet. 1999 Jun;64(6):1570-9. PMID:10330344 doi:10.1086/302422
- ↑ Yotsumoto S, Setoyama M, Hozumi H, Mizoguchi S, Fukumaru S, Kobayashi K, Saheki T, Kanzaki T. A novel point mutation affecting the tyrosine kinase domain of the TRKA gene in a family with congenital insensitivity to pain with anhidrosis. J Invest Dermatol. 1999 May;112(5):810-4. PMID:10233776 doi:10.1046/j.1523-1747.1999.00569.x
- ↑ Shatzky S, Moses S, Levy J, Pinsk V, Hershkovitz E, Herzog L, Shorer Z, Luder A, Parvari R. Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli-Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF receptor gene, clinical findings, and results of nerve conduction studies. Am J Med Genet. 2000 Jun 19;92(5):353-60. PMID:10861667
- ↑ Miura Y, Mardy S, Awaya Y, Nihei K, Endo F, Matsuda I, Indo Y. Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families. Hum Genet. 2000 Jan;106(1):116-24. PMID:10982191
- ↑ Greco A, Villa R, Fusetti L, Orlandi R, Pierotti MA. The Gly571Arg mutation, associated with the autonomic and sensory disorder congenital insensitivity to pain with anhidrosis, causes the inactivation of the NTRK1/nerve growth factor receptor. J Cell Physiol. 2000 Jan;182(1):127-33. PMID:10567924 doi:<127::AID-JCP14>3.0.CO;2-0 10.1002/(SICI)1097-4652(200001)182:1<127::AID-JCP14>3.0.CO;2-0
- ↑ Houlden H, King RH, Hashemi-Nejad A, Wood NW, Mathias CJ, Reilly M, Thomas PK. A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V. Ann Neurol. 2001 Apr;49(4):521-5. PMID:11310631
- ↑ Mardy S, Miura Y, Endo F, Matsuda I, Indo Y. Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor. Hum Mol Genet. 2001 Feb 1;10(3):179-88. PMID:11159935
- ↑ Davidson G, Murphy S, Polke J, Laura M, Salih M, Muntoni F, Blake J, Brandner S, Davies N, Horvath R, Price S, Donaghy M, Roberts M, Foulds N, Ramdharry G, Soler D, Lunn M, Manji H, Davis M, Houlden H, Reilly M. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. J Neurol. 2012 Aug;259(8):1673-85. PMID:22302274 doi:10.1007/s00415-011-6397-y
- ↑ Hempstead BL, Martin-Zanca D, Kaplan DR, Parada LF, Chao MV. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature. 1991 Apr 25;350(6320):678-83. PMID:1850821 doi:http://dx.doi.org/10.1038/350678a0
- ↑ Klein R, Jing SQ, Nanduri V, O'Rourke E, Barbacid M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell. 1991 Apr 5;65(1):189-97. PMID:1849459
- ↑ Barker PA, Lomen-Hoerth C, Gensch EM, Meakin SO, Glass DJ, Shooter EM. Tissue-specific alternative splicing generates two isoforms of the trkA receptor. J Biol Chem. 1993 Jul 15;268(20):15150-7. PMID:8325889
- ↑ Stephens RM, Loeb DM, Copeland TD, Pawson T, Greene LA, Kaplan DR. Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses. Neuron. 1994 Mar;12(3):691-705. PMID:8155326
- ↑ Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J. The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor. J Biol Chem. 2001 Mar 16;276(11):7709-12. Epub 2001 Jan 22. PMID:11244088 doi:10.1074/jbc.C000869200
- ↑ Tacconelli A, Farina AR, Cappabianca L, Desantis G, Tessitore A, Vetuschi A, Sferra R, Rucci N, Argenti B, Screpanti I, Gulino A, Mackay AR. TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Cancer Cell. 2004 Oct;6(4):347-60. PMID:15488758 doi:10.1016/j.ccr.2004.09.011
- ↑ Hempstead BL, Martin-Zanca D, Kaplan DR, Parada LF, Chao MV. High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature. 1991 Apr 25;350(6320):678-83. PMID:1850821 doi:http://dx.doi.org/10.1038/350678a0
- ↑ Klein R, Jing SQ, Nanduri V, O'Rourke E, Barbacid M. The trk proto-oncogene encodes a receptor for nerve growth factor. Cell. 1991 Apr 5;65(1):189-97. PMID:1849459
- ↑ Barker PA, Lomen-Hoerth C, Gensch EM, Meakin SO, Glass DJ, Shooter EM. Tissue-specific alternative splicing generates two isoforms of the trkA receptor. J Biol Chem. 1993 Jul 15;268(20):15150-7. PMID:8325889
- ↑ Stephens RM, Loeb DM, Copeland TD, Pawson T, Greene LA, Kaplan DR. Trk receptors use redundant signal transduction pathways involving SHC and PLC-gamma 1 to mediate NGF responses. Neuron. 1994 Mar;12(3):691-705. PMID:8155326
- ↑ Wooten MW, Seibenhener ML, Mamidipudi V, Diaz-Meco MT, Barker PA, Moscat J. The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor. J Biol Chem. 2001 Mar 16;276(11):7709-12. Epub 2001 Jan 22. PMID:11244088 doi:10.1074/jbc.C000869200
- ↑ Tacconelli A, Farina AR, Cappabianca L, Desantis G, Tessitore A, Vetuschi A, Sferra R, Rucci N, Argenti B, Screpanti I, Gulino A, Mackay AR. TrkA alternative splicing: a regulated tumor-promoting switch in human neuroblastoma. Cancer Cell. 2004 Oct;6(4):347-60. PMID:15488758 doi:10.1016/j.ccr.2004.09.011
- ↑ Stachel SJ, Sanders JM, Henze DA, Rudd MT, Su HP, Li Y, Nanda KK, Egbertson MS, Manley PJ, Jones KL, Brnardic EJ, Green A, Grobler JA, Hanney B, Leitl M, Lai MT, Munshi V, Murphy D, Rickert K, Riley D, Krasowska-Zoladek A, Daley C, Zuck P, Kane SA, Bilodeau M. Maximizing Diversity from a Kinase Screen: Identification of Novel and Selective pan-Trk Inhibitors for Chronic Pain. J Med Chem. 2014 Jun 10. PMID:24914455 doi:http://dx.doi.org/10.1021/jm5006429
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