6dkg - Revision history

OCA at 14:35, 13 March 2024

2024-03-13T14:35:12Z

←Older revision		Revision as of 14:35, 13 March 2024
Line 1:		Line 1:

	==Crystal structure of Trk-A in complex with the Pan-Trk Kinase Inhibitor, compound 13b.==		==Crystal structure of Trk-A in complex with the Pan-Trk Kinase Inhibitor, compound 13b.==
-	<StructureSection load='6dkg' size='340' side='right' caption='[[6dkg]], [[Resolution\|resolution]] 2.53Å' scene=''>	+	<StructureSection load='6dkg' size='340' side='right'caption='[[6dkg]], [[Resolution\|resolution]] 2.53Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6dkg]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DKG OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6DKG FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6dkg]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DKG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DKG FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=22L:5-PHENYLTHIENO[2,3-D]PYRIMIDIN-4(3H)-ONE'>22L</scene>, <scene name='pdbligand=GO7:2-{[(3R,4S)-3-fluoro-1-{[4-(trifluoromethoxy)phenyl]acetyl}piperidin-4-yl]oxy}-4-(2-hydroxy-2-methylpropoxy)benzamide'>GO7</scene~~></td></tr>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.53Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6dkb\|6dkb]]</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=22L:5-PHENYLTHIENO[2,3-D]PYRIMIDIN-4(3H)-ONE'>22L</scene>, <scene name='pdbligand=GO7:2-{[(3R,4S)-3-fluoro-1-{[4-(trifluoromethoxy)phenyl]acetyl}piperidin-4-yl]oxy}-4-(2-hydroxy-2-methylpropoxy)benzamide'>GO7</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NTRK1, MTC, TRK, TRKA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6dkg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dkg OCA], [https://pdbe.org/6dkg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dkg RCSB], [https://www.ebi.ac.uk/pdbsum/6dkg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dkg ProSAT]</span></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>	+
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6dkg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dkg OCA], [~~http~~://pdbe.org/6dkg PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6dkg RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6dkg PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6dkg ProSAT]</span></td></tr>	+
	</table>		</table>
	== Disease ==		== Disease ==
-	[~~[http~~://www.uniprot.org/uniprot/NTRK1_HUMAN NTRK1_HUMAN]] Defects in NTRK1 are a cause of congenital insensitivity to pain with anhidrosis (CIPA) [MIM:[~~http~~://omim.org/entry/256800 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.<ref>PMID:8696348</ref> <ref>PMID:10090906</ref> <ref>PMID:10330344</ref> <ref>PMID:10233776</ref> <ref>PMID:10861667</ref> <ref>PMID:10982191</ref> <ref>PMID:10567924</ref> <ref>PMID:11310631</ref> <ref>PMID:11159935</ref> <ref>PMID:22302274</ref> Defects in NTRK1 are a cause of thyroid papillary carcinoma (TPC) [MIM:[~~http~~://omim.org/entry/188550 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.	+	[https://www.uniprot.org/uniprot/NTRK1_HUMAN NTRK1_HUMAN] Defects in NTRK1 are a cause of congenital insensitivity to pain with anhidrosis (CIPA) [MIM:[https://omim.org/entry/256800 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.<ref>PMID:8696348</ref> <ref>PMID:10090906</ref> <ref>PMID:10330344</ref> <ref>PMID:10233776</ref> <ref>PMID:10861667</ref> <ref>PMID:10982191</ref> <ref>PMID:10567924</ref> <ref>PMID:11310631</ref> <ref>PMID:11159935</ref> <ref>PMID:22302274</ref> Defects in NTRK1 are a cause of thyroid papillary carcinoma (TPC) [MIM:[https://omim.org/entry/188550 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 ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/NTRK1_HUMAN 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.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref> 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.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref>	+	[https://www.uniprot.org/uniprot/NTRK1_HUMAN 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.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref> 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.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4) are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein we discuss the discovery of two potent, selective, peripherally restricted, efficacious and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.	+

-	Discovery of Potent, Selective and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain.,Bagal SK, Andrews M, Bechle BM, Bian J, Bilsland J, Blakemore DC, Braganza J, Bungay PJ, Corbett MS, Cronin CN, Cui JJ, Dias R, Flanagan NJ, Greasley SE, Grimley R, James K, Johnson E, Kitching L, Kraus ML, McAlpine I, Nagata A, Ninkovic S, Omoto K, Scales S, Skerratt SE, Sun J, Tran-Dube M, Waldron GJ, Wang F, Warmus JS J Med Chem. 2018 Jun 26. doi: 10.1021/acs.jmedchem.8b00633. PMID:29944371<ref>PMID:29944371</ref>	+	==See Also==
-		+	*[[High affinity nerve growth factor receptor\|High affinity nerve growth factor receptor]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+	*[[Tyrosine kinase receptor 3D structures\|Tyrosine kinase receptor 3D structures]]
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 6dkg" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Receptor protein-tyrosine kinase~~]]	+	[[Category: Large Structures]]
-	[[Category: Cronin~~, C N~~]]	+	[[Category: Cronin CN]]
-	[[Category: Greasley~~, S E~~]]	+	[[Category: Greasley SE]]
-	[[Category: Johnson, E]]	+	[[Category: Johnson E]]
-	[[Category: Kraus~~, M L]]~~	+	[[Category: Kraus ML]]
-	~~[[Category: Inhibitor tyrosine kinase]]~~	+
-	~~[[Category: Pan-trk kinase]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex]]~~	+
-	~~[[Category: Treatment for pain~~]]	+

OCA at 16:39, 15 August 2018

2018-08-15T16:39:39Z

←Older revision		Revision as of 16:39, 15 August 2018
Line 3:		Line 3:
	<StructureSection load='6dkg' size='340' side='right' caption='[[6dkg]], [[Resolution\|resolution]] 2.53Å' scene=''>		<StructureSection load='6dkg' size='340' side='right' caption='[[6dkg]], [[Resolution\|resolution]] 2.53Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6dkg]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DKG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DKG FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6dkg]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DKG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DKG FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=22L:5-PHENYLTHIENO[2,3-D]PYRIMIDIN-4(3H)-ONE'>22L</scene>, <scene name='pdbligand=GO7:2-{[(3R,4S)-3-fluoro-1-{[4-(trifluoromethoxy)phenyl]acetyl}piperidin-4-yl]oxy}-4-(2-hydroxy-2-methylpropoxy)benzamide'>GO7</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=22L:5-PHENYLTHIENO[2,3-D]PYRIMIDIN-4(3H)-ONE'>22L</scene>, <scene name='pdbligand=GO7:2-{[(3R,4S)-3-fluoro-1-{[4-(trifluoromethoxy)phenyl]acetyl}piperidin-4-yl]oxy}-4-(2-hydroxy-2-methylpropoxy)benzamide'>GO7</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6dkb\|6dkb]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6dkb\|6dkb]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">NTRK1, MTC, TRK, TRKA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dkg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dkg OCA], [http://pdbe.org/6dkg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dkg RCSB], [http://www.ebi.ac.uk/pdbsum/6dkg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dkg ProSAT]</span></td></tr>		<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dkg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dkg OCA], [http://pdbe.org/6dkg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dkg RCSB], [http://www.ebi.ac.uk/pdbsum/6dkg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dkg ProSAT]</span></td></tr>
Line 26:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Receptor protein-tyrosine kinase]]		[[Category: Receptor protein-tyrosine kinase]]
	[[Category: Cronin, C N]]		[[Category: Cronin, C N]]

OCA at 05:44, 11 July 2018

2018-07-11T05:44:17Z

←Older revision		Revision as of 05:44, 11 July 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6dkg is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==Crystal structure of Trk-A in complex with the Pan-Trk Kinase Inhibitor, compound 13b.==
		+	<StructureSection load='6dkg' size='340' side='right' caption='[[6dkg]], [[Resolution\|resolution]] 2.53Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6dkg]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DKG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DKG FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=22L:5-PHENYLTHIENO[2,3-D]PYRIMIDIN-4(3H)-ONE'>22L</scene>, <scene name='pdbligand=GO7:2-{[(3R,4S)-3-fluoro-1-{[4-(trifluoromethoxy)phenyl]acetyl}piperidin-4-yl]oxy}-4-(2-hydroxy-2-methylpropoxy)benzamide'>GO7</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6dkb\|6dkb]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] </span></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6dkg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dkg OCA], [http://pdbe.org/6dkg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dkg RCSB], [http://www.ebi.ac.uk/pdbsum/6dkg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dkg ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[[http://www.uniprot.org/uniprot/NTRK1_HUMAN NTRK1_HUMAN]] Defects in NTRK1 are a cause of congenital insensitivity to pain with anhidrosis (CIPA) [MIM:[http://omim.org/entry/256800 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.<ref>PMID:8696348</ref> <ref>PMID:10090906</ref> <ref>PMID:10330344</ref> <ref>PMID:10233776</ref> <ref>PMID:10861667</ref> <ref>PMID:10982191</ref> <ref>PMID:10567924</ref> <ref>PMID:11310631</ref> <ref>PMID:11159935</ref> <ref>PMID:22302274</ref> Defects in NTRK1 are a cause of thyroid papillary carcinoma (TPC) [MIM:[http://omim.org/entry/188550 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 ==
		+	[[http://www.uniprot.org/uniprot/NTRK1_HUMAN 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.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref> 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.<ref>PMID:1850821</ref> <ref>PMID:1849459</ref> <ref>PMID:8325889</ref> <ref>PMID:8155326</ref> <ref>PMID:11244088</ref> <ref>PMID:15488758</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Hormones of the neurotrophin family: nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4) are known to activate the family of Tropomyosin receptor kinases (TrkA, TrkB, TrkC). Moreover, inhibition of the TrkA kinase pathway in pain has been clinically validated by the NGF antibody tanezumab leading to significant interest in the development of small molecule inhibitors of TrkA. Furthermore, Trk inhibitors having an acceptable safety profile will require minimal brain availability. Herein we discuss the discovery of two potent, selective, peripherally restricted, efficacious and well-tolerated series of pan-Trk inhibitors which successfully delivered three candidate quality compounds 10b, 13b and 19. All three compounds are predicted to possess low metabolic clearance in human that does not proceed via aldehyde oxidase-catalyzed reactions, thus addressing the potential clearance prediction liability associated with our current pan-Trk development candidate PF-06273340.

-	~~Authors: Greasley~~, ~~S.E~~., ~~Johnson~~, E., Kraus, M~~.L.~~, ~~Cronin~~, C.N.	+	Discovery of Potent, Selective and Peripherally Restricted Pan-Trk Kinase Inhibitors for the Treatment of Pain.,Bagal SK, Andrews M, Bechle BM, Bian J, Bilsland J, Blakemore DC, Braganza J, Bungay PJ, Corbett MS, Cronin CN, Cui JJ, Dias R, Flanagan NJ, Greasley SE, Grimley R, James K, Johnson E, Kitching L, Kraus ML, McAlpine I, Nagata A, Ninkovic S, Omoto K, Scales S, Skerratt SE, Sun J, Tran-Dube M, Waldron GJ, Wang F, Warmus JS J Med Chem. 2018 Jun 26. doi: 10.1021/acs.jmedchem.8b00633. PMID:29944371<ref>PMID:29944371</ref>

-	~~Description: Crystal structure~~ of ~~Trk-A in complex with~~ the ~~Pan-Trk Kinase Inhibitor, compound 13b~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: ~~Kraus~~, ~~M.L~~]]	+	<div class="pdbe-citations 6dkg" style="background-color:#fffaf0;"></div>
-	[[Category: Greasley, S.E]]	+	== References ==
-	~~[[Category: Cronin, C.N~~]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Receptor protein-tyrosine kinase]]
		+	[[Category: Cronin, C N]]
		+	[[Category: Greasley, S E]]
	[[Category: Johnson, E]]		[[Category: Johnson, E]]
		+	[[Category: Kraus, M L]]
		+	[[Category: Inhibitor tyrosine kinase]]
		+	[[Category: Pan-trk kinase]]
		+	[[Category: Transferase]]
		+	[[Category: Transferase-transferase inhibitor complex]]
		+	[[Category: Treatment for pain]]

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-	The entry 6dkg is ON HOLD	+	The entry 6dkg is ON HOLD until Paper Publication

	Authors: Greasley, S.E., Johnson, E., Kraus, M.L., Cronin, C.N.		Authors: Greasley, S.E., Johnson, E., Kraus, M.L., Cronin, C.N.

OCA: Protected "6dkg" [edit=sysop:move=sysop]

2018-06-06T04:22:38Z

Protected "6dkg" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:22, 6 June 2018

OCA: New page: '''Unreleased structure''' The entry 6dkg is ON HOLD Authors: Greasley, S.E., Johnson, E., Kraus, M.L., Cronin, C.N. Description: Crystal structure of Trk-A in complex with the Pan-Trk...

2018-06-06T04:22:37Z

New page: '''Unreleased structure''' The entry 6dkg is ON HOLD Authors: Greasley, S.E., Johnson, E., Kraus, M.L., Cronin, C.N. Description: Crystal structure of Trk-A in complex with the Pan-Trk...

New page

'''Unreleased structure'''

The entry 6dkg is ON HOLD

Authors: Greasley, S.E., Johnson, E., Kraus, M.L., Cronin, C.N.

Description: Crystal structure of Trk-A in complex with the Pan-Trk Kinase Inhibitor, compound 13b.
[[Category: Unreleased Structures]]
[[Category: Kraus, M.L]]
[[Category: Greasley, S.E]]
[[Category: Cronin, C.N]]
[[Category: Johnson, E]]