View source for 6tpe


==Fragment-based discovery of pyrazolopyridones as JAK1 inhibitors with excellent subtype selectivity==
<StructureSection load='6tpe' size='340' side='right'caption='[[6tpe]], [[Resolution|resolution]] 2.87&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TPE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TPE 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]] 2.87&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NTW:2-[4-(3-methyl-6-oxidanylidene-1,7-dihydropyrazolo[3,4-b]pyridin-4-yl)cyclohexyl]ethanenitrile'>NTW</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=6tpe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tpe OCA], [https://pdbe.org/6tpe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tpe RCSB], [https://www.ebi.ac.uk/pdbsum/6tpe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tpe ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Herein, we report the discovery of a series of JAK1-selective kinase inhibitors with high potency and excellent JAK family subtype selectivity. A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was selected as the starting point for our fragment-based lead generation efforts. A two-stage strategy was chosen with the dual aims of improving potency and JAK1 selectivity: Optimization of the lipophilic ribose pocket-targeting substituent was followed by the introduction of a variety of P-loop-targeting functional groups. Combining the best moieties from both stages of the optimization afforded compound 40, which showed excellent potency and selectivity. Metabolism studies in vitro and in vivo together with an in vitro safety evaluation suggest that 40 may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors.

Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity.,Hansen BB, Jepsen TH, Larsen M, Sindet R, Vifian T, Burhardt MN, Larsen J, Seitzberg JG, Carnerup MA, Jerre A, Molck C, Lovato P, Rai S, Nasipireddy VR, Ritzen A J Med Chem. 2020 Jun 8. doi: 10.1021/acs.jmedchem.0c00359. PMID:32462873<ref>PMID:32462873</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6tpe" style="background-color:#fffaf0;"></div>

==See Also==
*[[Janus kinase 3D structures|Janus kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Burhardt MN]]
[[Category: Carnerup MA]]
[[Category: Hansen BB]]
[[Category: Jepsen TH]]
[[Category: Jerre A]]
[[Category: Jestel A]]
[[Category: Lammens A]]
[[Category: Larsen J]]
[[Category: Larsen M]]
[[Category: Molck C]]
[[Category: Nasipireddy VR]]
[[Category: Rai S]]
[[Category: Ritzen A]]
[[Category: Seitzberg JG]]
[[Category: Sindet R]]
[[Category: Vifian T]]