6yi8: Difference between revisions
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<StructureSection load='6yi8' size='340' side='right'caption='[[6yi8]], [[Resolution|resolution]] 2.13Å' scene=''> | <StructureSection load='6yi8' size='340' side='right'caption='[[6yi8]], [[Resolution|resolution]] 2.13Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6YI8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YI8 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]] 2.13Å</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]] 2.13Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FGF:N-[5-cyano-4-(2-methoxyethylamino)pyridin-2-yl]-7-methanoyl-6-[(4-methyl-2-oxidanylidene-piperazin-1-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide'>FGF</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FGF:N-[5-cyano-4-(2-methoxyethylamino)pyridin-2-yl]-7-methanoyl-6-[(4-methyl-2-oxidanylidene-piperazin-1-yl)methyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxamide'>FGF</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6yi8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yi8 OCA], [https://pdbe.org/6yi8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yi8 RCSB], [https://www.ebi.ac.uk/pdbsum/6yi8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yi8 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=6yi8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yi8 OCA], [https://pdbe.org/6yi8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yi8 RCSB], [https://www.ebi.ac.uk/pdbsum/6yi8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yi8 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Ostermann N]] | [[Category: Ostermann N]] | ||
Latest revision as of 12:17, 9 October 2024
HUMAN FGFR4 KINASE DOMAIN (447-753) IN COMPLEX WITH ROBLITINIBHUMAN FGFR4 KINASE DOMAIN (447-753) IN COMPLEX WITH ROBLITINIB
Structural highlights
Publication Abstract from PubMedFGF19 signaling through the FGFR4/beta-klotho receptor complex has been shown to be a key driver of growth and survival in a subset of hepatocellular carcinomas making selective FGFR4 inhibition an attractive treatment opportunity. A kinome-wide sequence alignment highlighted a poorly-conserved cysteine residue within the FGFR4 ATP-binding site at position 552, two positions beyond the gate-keeper residue. Several strategies for targeting this cysteine to identify FGFR4 selective inhibitor starting points are summarised which made use of both rationale and unbiased screening approaches. The optimisation of a 2-formylquinoline amide hit series is described in which the aldehyde makes a hemithioacetal reversible-covalent interaction with cysteine 552. Key challenges addressed during the optimisation are improving the FGFR4 potency, metabolic stability and solubility leading ultimately to the highly-selective first-in-class clinical candidate roblitinib. Discovery of Roblitinib (FGF401) as a Reversible-Covalent Inhibitor of the Kinase Activity of Fibroblast Growth Factor Receptor 4.,Fairhurst RA, Knoepfel T, Buschmann N, Leblanc C, Mah R, Todorov M, Nimsgern P, Ripoche S, Niklaus M, Warin N, Luu VH, Madoerin M, Wirth J, Graus-Porta D, Weiss A, Kiffe M, Wartmann M, Kinyamu-Akunda J, Sterker D, Stamm C, Adler F, Buhles A, Schadt H, Couttet P, Blank J, Galuba I, Trappe J, Voshol J, Ostermann N, Zou C, Berghausen J, Del Rio Espinola A, Jahnke W, Furet P J Med Chem. 2020 Sep 15. doi: 10.1021/acs.jmedchem.0c01019. PMID:32930584[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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