View source for 7wcw


==Crystal structure of FGFR4(V550L) kinase domain with 7v==
<StructureSection load='7wcw' size='340' side='right'caption='[[7wcw]], [[Resolution|resolution]] 2.32&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7WCW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7WCW 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]] 2.317&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=90F:~{N}-[2-[[5-[(1~{R})-1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-1~{H}-indazol-3-yl]amino]-3-fluoranyl-5-(4-morpholin-4-ylpiperidin-1-yl)phenyl]propanamide'>90F</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=7wcw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7wcw OCA], [https://pdbe.org/7wcw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7wcw RCSB], [https://www.ebi.ac.uk/pdbsum/7wcw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7wcw ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Aberrant FGF19/FGFR4 signaling has been shown to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC) with several pan-FGFR inhibitors and FGFR4-selective inhibitors currently being evaluated in the clinic. However, FGFR4 gatekeeper mutation induced acquired resistance remains an unmet clinical challenge for HCC treatment. Thus, a series of aminoindazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. One representative compound (7v) exhibited excellent potency against FGFR4, FGFR4(V550L), and FGFR4(V550M) with nanomolar activity in both the biochemical and cellular assays while sparing FGFR1/2/3. While compound 7v demonstrated modest in vivo antitumor efficacy in nude mice bearing the Huh-7 xenograft model consistent with its unfavorable pharmacokinetic properties, it provides a promising new starting point for future drug discovery combating FGFR4 gatekeeper mediated resistance in HCC patients.

Design, Synthesis, and Biological Evaluation of Aminoindazole Derivatives as Highly Selective Covalent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR4.,Shao M, Chen X, Yang F, Song X, Zhou Y, Lin Q, Fu Y, Ortega R, Lin X, Tu Z, Patterson AV, Smaill JB, Chen Y, Lu X J Med Chem. 2022 Mar 24;65(6):5113-5133. doi: 10.1021/acs.jmedchem.2c00096. Epub , 2022 Mar 10. PMID:35271262<ref>PMID:35271262</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7wcw" style="background-color:#fffaf0;"></div>

==See Also==
*[[Fibroblast growth factor receptor 3D receptor|Fibroblast growth factor receptor 3D receptor]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Chen XJ]]
[[Category: Chen YH]]
[[Category: Dai SY]]
[[Category: Lin QM]]