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==Structure of DYRK1A in complex with compound 32== | ==Structure of DYRK1A in complex with compound 32== | ||
<StructureSection load='7ajm' size='340' side='right'caption='[[7ajm]]' scene=''> | <StructureSection load='7ajm' size='340' side='right'caption='[[7ajm]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AJM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AJM FirstGlance]. <br> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AJM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AJM FirstGlance]. <br> | ||
</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=7ajm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ajm OCA], [https://pdbe.org/7ajm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ajm RCSB], [https://www.ebi.ac.uk/pdbsum/7ajm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ajm ProSAT]</span></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]] 2.4Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene>, <scene name='pdbligand=RKW:~{N}-[6-azanyl-4-(1-benzofuran-5-yl)pyridin-2-yl]-2-(methylamino)ethanamide'>RKW</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=7ajm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ajm OCA], [https://pdbe.org/7ajm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ajm RCSB], [https://www.ebi.ac.uk/pdbsum/7ajm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ajm ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma. | |||
Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors.,Weber C, Sipos M, Paczal A, Balint B, Kun V, Foloppe N, Dokurno P, Massey AJ, Walmsley DL, Hubbard RE, Murray J, Benwell K, Edmonds T, Demarles D, Bruno A, Burbridge M, Cruzalegui F, Kotschy A J Med Chem. 2021 May 12. doi: 10.1021/acs.jmedchem.1c00023. PMID:33975430<ref>PMID:33975430</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7ajm" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||