View source for 4ivc


==JAK1 kinase (JH1 domain) in complex with the inhibitor (TRANS-4-{2-[(1R)-1-HYDROXYETHYL]IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(6H)-YL}CYCLOHEXYL)ACETONITRILE==
<StructureSection load='4ivc' size='340' side='right'caption='[[4ivc]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4ivc]] 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=4IVC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4IVC 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]] 2.35&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1J6:(TRANS-4-{2-[(1R)-1-HYDROXYETHYL]IMIDAZO[4,5-D]PYRROLO[2,3-B]PYRIDIN-1(6H)-YL}CYCLOHEXYL)ACETONITRILE'>1J6</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=4ivc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ivc OCA], [https://pdbe.org/4ivc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ivc RCSB], [https://www.ebi.ac.uk/pdbsum/4ivc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ivc ProSAT]</span></td></tr>
</table>
== Function ==
[https://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.
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== Publication Abstract from PubMed ==
Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model.

Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2.,Zak M, Hurley CA, Ward SI, Bergeron P, Barrett K, Balazs M, Blair WS, Bull R, Chakravarty P, Chang C, Crackett P, Deshmukh G, Devoss J, Dragovich PS, Eigenbrot C, Ellwood C, Gaines S, Ghilardi N, Gibbons P, Gradl S, Gribling P, Hamman C, Harstad E, Hewitt P, Johnson A, Johnson T, Kenny JR, Koehler MF, Bir Kohli P, Labadie S, Lee WP, Liao J, Liimatta M, Mendonca R, Narukulla R, Pulk R, Reeve A, Savage S, Shia S, Steffek M, Ubhayakar S, van Abbema A, Aliagas I, Avitabile-Woo B, Xiao Y, Yang J, Kulagowski JJ J Med Chem. 2013 Jun 13;56(11):4764-85. doi: 10.1021/jm4004895. Epub 2013 May 31. PMID:23659214<ref>PMID:23659214</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 4ivc" 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: Eigenbrot C]]
[[Category: Shia S]]