5wo4: Difference between revisions

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-'''Unreleased structure'''
-The entry 5wo4 is ON HOLD  until Paper Publication
+==JAK1 complexed with compound 28==
+<StructureSection load='5wo4' size='340' side='right' caption='[[5wo4]], [[Resolution|resolution]] 1.84&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5wo4]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WO4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WO4 FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B7V:3-[(4-chloro-3-methoxyphenyl)amino]-1-[(3R,4S)-4-cyanooxan-3-yl]-1H-pyrazole-4-carboxamide'>B7V</scene></td></tr>
+<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=5wo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wo4 OCA], [http://pdbe.org/5wo4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wo4 RCSB], [http://www.ebi.ac.uk/pdbsum/5wo4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wo4 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://www.uniprot.org/uniprot/JAK1_HUMAN JAK1_HUMAN]] Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28.
-Authors:
+The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1 H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties.,Siu T, Brubaker J, Fuller P, Torres L, Zeng H, Close J, Mampreian DM, Shi F, Liu D, Fradera X, Johnson K, Bays N, Kadic E, He F, Goldenblatt P, Shaffer L, Patel SB, Lesburg CA, Alpert C, Dorosh L, Deshmukh SV, Yu H, Klappenbach J, Elwood F, Dinsmore CJ, Fernandez R, Moy L, Young JR J Med Chem. 2017 Dec 4. doi: 10.1021/acs.jmedchem.7b01135. PMID:29156136<ref>PMID:29156136</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5wo4" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Non-specific protein-tyrosine kinase]]
+[[Category: Lesburg, C A]]
+[[Category: Patel, S B]]
+[[Category: Protein tyrosine kinase]]
+[[Category: Transferase]]