4ymj: Difference between revisions
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==(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors== | ==(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors== | ||
<StructureSection load='4ymj' size='340' side='right' caption='[[4ymj]], [[Resolution|resolution]] 2.00Å' scene=''> | <StructureSection load='4ymj' size='340' side='right'caption='[[4ymj]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4ymj]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YMJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YMJ FirstGlance]. <br> | <table><tr><td colspan='2'>[[4ymj]] is a 2 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=4YMJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YMJ FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4EJ:4-[6-(BENZYLAMINO)IMIDAZO[1,2-B]PYRIDAZIN-3-YL]BENZONITRILE'>4EJ</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4EJ:4-[6-(BENZYLAMINO)IMIDAZO[1,2-B]PYRIDAZIN-3-YL]BENZONITRILE'>4EJ</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | ||
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NTRK3, TRKC ([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=4ymj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ymj OCA], [http://pdbe.org/4ymj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ymj RCSB], [http://www.ebi.ac.uk/pdbsum/4ymj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ymj 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=4ymj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ymj OCA], [http://pdbe.org/4ymj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ymj RCSB], [http://www.ebi.ac.uk/pdbsum/4ymj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ymj ProSAT]</span></td></tr> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Receptor protein-tyrosine kinase]] | [[Category: Receptor protein-tyrosine kinase]] | ||
[[Category: Kreusch, A]] | [[Category: Kreusch, A]] | ||
Revision as of 09:43, 12 June 2019
(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors(R)-2-Phenylpyrrolidine Substitute Imidazopyridazines: a New Class of Potent and Selective Pan-TRK Inhibitors
Structural highlights
Function[NTRK3_HUMAN] Receptor for neurotrophin-3 (NT-3). This is a tyrosine-protein kinase receptor. Known substrates for the trk receptors are SHC1, PI-3 kinase, and PLCG1. The different isoforms do not have identical signaling properties. Publication Abstract from PubMedDeregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs. (R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors.,Choi HS, Rucker PV, Wang Z, Fan Y, Albaugh P, Chopiuk G, Gessier F, Sun F, Adrian F, Liu G, Hood T, Li N, Jia Y, Che J, McCormack S, Li A, Li J, Steffy A, Culazzo A, Tompkins C, Phung V, Kreusch A, Lu M, Hu B, Chaudhary A, Prashad M, Tuntland T, Liu B, Harris J, Seidel HM, Loren J, Molteni V ACS Med Chem Lett. 2015 Mar 16;6(5):562-7. doi: 10.1021/acsmedchemlett.5b00050., eCollection 2015 May 14. PMID:26005534[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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