4e6q: Difference between revisions
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==JAK2 kinase (JH1 domain) triple mutant in complex with compound 12== | |||
<StructureSection load='4e6q' size='340' side='right'caption='[[4e6q]], [[Resolution|resolution]] 1.95Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4e6q]] is a 2 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=4E6Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4E6Q FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.948Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0NV:1-(1-BENZYLPIPERIDIN-4-YL)-1,6-DIHYDROIMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDINE'>0NV</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></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=4e6q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4e6q OCA], [https://pdbe.org/4e6q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4e6q RCSB], [https://www.ebi.ac.uk/pdbsum/4e6q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4e6q ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogs demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of sub-nanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogs to enhance affinity and selectivity. | |||
Identification of Imidazo-pyrrolopyridines as Novel and Potent JAK1 Inhibitors.,Kulagowski J J Med Chem. 2012 May 16. PMID:22591402<ref>PMID:22591402</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4e6q" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Janus kinase 3D structures|Janus kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Murray JM]] | |||
Latest revision as of 05:49, 21 November 2024
JAK2 kinase (JH1 domain) triple mutant in complex with compound 12JAK2 kinase (JH1 domain) triple mutant in complex with compound 12
Structural highlights
Publication Abstract from PubMedA therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogs demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of sub-nanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogs to enhance affinity and selectivity. Identification of Imidazo-pyrrolopyridines as Novel and Potent JAK1 Inhibitors.,Kulagowski J J Med Chem. 2012 May 16. PMID:22591402[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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