6smb: Difference between revisions
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<StructureSection load='6smb' size='340' side='right'caption='[[6smb]], [[Resolution|resolution]] 2.04Å' scene=''> | <StructureSection load='6smb' size='340' side='right'caption='[[6smb]], [[Resolution|resolution]] 2.04Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SMB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SMB FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LKQ:~{N}-[3-[2-[(3-methoxy-1-methyl-pyrazol-4-yl)amino]-5-methyl-pyrimidin-4-yl]-1~{H}-indol-7-yl]-2-methyl-pyridine-3-carboxamide'>LKQ</scene> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.04Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LKQ:~{N}-[3-[2-[(3-methoxy-1-methyl-pyrazol-4-yl)amino]-5-methyl-pyrimidin-4-yl]-1~{H}-indol-7-yl]-2-methyl-pyridine-3-carboxamide'>LKQ</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=6smb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6smb OCA], [https://pdbe.org/6smb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6smb RCSB], [https://www.ebi.ac.uk/pdbsum/6smb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6smb ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6smb" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6smb" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Janus kinase 3D structures|Janus kinase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Read JA]] | |||
[[Category: Read | [[Category: Steuber H]] | ||
[[Category: Steuber | |||
Latest revision as of 08:47, 21 November 2024
Human jak1 kinase domain in complex with inhibitorHuman jak1 kinase domain in complex with inhibitor
Structural highlights
Publication Abstract from PubMedJAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases. Particularly, pSTAT3 is observed in response to the treatment with inhibitors of oncogenic signaling pathways such as EGFR, MAPK, and AKT and is associated with resistance or poorer response to agents targeting these pathways. Among the JAK family kinases, JAK1 has been shown to be the primary driver of STAT3 phosphorylation and signaling; therefore, selective JAK1 inhibition can be a viable means to overcome such treatment resistances. Herein, an account of the medicinal chemistry optimization from the promiscuous kinase screening hit 3 to the candidate drug 21 (AZD4205), a highly selective JAK1 kinase inhibitor, is reported. Compound 21 has good preclinical pharmacokinetics. Compound 21 displayed an enhanced antitumor activity in combination with an approved EGFR inhibitor, osimertinib, in a preclinical non-small-cell lung cancer (NSCLC) xenograft NCI-H1975 model. Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-y l]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a Potent and Selective Janus Kinase 1 Inhibitor.,Su Q, Banks E, Bebernitz G, Bell K, Borenstein CF, Chen H, Chuaqui CE, Deng N, Ferguson AD, Kawatkar S, Grimster NP, Ruston L, Lyne PD, Read JA, Peng X, Pei X, Fawell S, Tang Z, Throner S, Vasbinder MM, Wang H, Winter-Holt J, Woessner R, Wu A, Yang W, Zinda M, Kettle JG J Med Chem. 2020 Apr 28. doi: 10.1021/acs.jmedchem.9b01392. PMID:32297743[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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