4gj3
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4gj3]] is a 1 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=4GJ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GJ3 FirstGlance]. <br> | <table><tr><td colspan='2'>[[4gj3]] is a 1 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=4GJ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GJ3 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0XP:2,6-DICHLORO-4-CYANO-N-[2-({[(1R,2R)-2-FLUOROCYCLOPROPYL]CARBONYL}AMINO)PYRIDIN-4-YL]BENZAMIDE'>0XP</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0XP:2,6-DICHLORO-4-CYANO-N-[2-({[(1R,2R)-2-FLUOROCYCLOPROPYL]CARBONYL}AMINO)PYRIDIN-4-YL]BENZAMIDE'>0XP</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=4gj3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gj3 OCA], [https://pdbe.org/4gj3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gj3 RCSB], [https://www.ebi.ac.uk/pdbsum/4gj3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gj3 ProSAT]</span></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=4gj3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gj3 OCA], [https://pdbe.org/4gj3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gj3 RCSB], [https://www.ebi.ac.uk/pdbsum/4gj3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gj3 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/TYK2_HUMAN TYK2_HUMAN] Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.<ref>PMID:7526154</ref> | [https://www.uniprot.org/uniprot/TYK2_HUMAN TYK2_HUMAN] Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.<ref>PMID:7526154</ref> | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-gamma (IFNgamma), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo. | ||
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| - | Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors.,Liang J, van Abbema A, Balazs M, Barrett K, Berezhkovsky L, Blair W, Chang C, Delarosa D, Devoss J, Driscoll J, Eigenbrot C, Ghilardi N, Gibbons P, Halladay J, Johnson A, Kohli PB, Lai Y, Liu Y, Lyssikatos J, Mantik P, Menghrajani K, Murray J, Peng I, Sambrone A, Shia S, Shin Y, Smith J, Sohn S, Tsui V, Ultsch M, Wu LC, Xiao Y, Yang W, Young J, Zhang B, Zhu BY, Magnuson S J Med Chem. 2013 Jun 13;56(11):4521-36. doi: 10.1021/jm400266t. Epub 2013 May 29. PMID:23668484<ref>PMID:23668484</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 4gj3" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
Current revision
Tyk2 (JH1) in complex with 2,6-dichloro-4-cyano-N-[2-({[(1R,2R)-2-fluorocyclopropyl]carbonyl}amino)pyridin-4-yl]benzamide
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