9u7s: Difference between revisions
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==FGFR2 kinase domain with a macrocyclic compound 8r== | |||
<StructureSection load='9u7s' size='340' side='right'caption='[[9u7s]], [[Resolution|resolution]] 1.99Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9u7s]] 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=9U7S OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9U7S 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]] 1.99Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=9u7s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9u7s OCA], [https://pdbe.org/9u7s PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9u7s RCSB], [https://www.ebi.ac.uk/pdbsum/9u7s PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9u7s ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Alterations in the FGFR family act as oncogenic drivers for multiple pediatric and adult tumors, leading to the development and approval of several FGFR inhibitors. However, the on-target gatekeeper and "molecular brake" mutations confer clinically acquired resistance to the FDA-approved FGFR inhibitors, which presents a significant unmet medical need. Herein, we report the first novel macrocycle-based FGFR inhibitors targeting both wild-type and clinically acquired variants of the FGFR family. The representative compound 8r potently inhibited FGFR1/2/3 with IC(50) values of 10.0, 6.9, and 30.2 nM, respectively. Compound 8r also potently suppressed proliferation of a series of FGFR-driven cancer cell lines with IC(50) values of 2.0-13.3 nM. Compared with futibatinib, 8r exhibited superior inhibitory activity toward FGFR1(V561M), FGFR2(V564F), and FGFR2(N549K) mutations with IC(50) values of 6.8, 0.7, and 0.8 nM, respectively. Moreover, 8r demonstrated favorable antitumor efficacy in an RT112/84 bladder cancer xenograft model. This work provides a promising macrocycle-based lead compound for the treatment of FGFR-driven cancers. | |||
Design, Synthesis, and Biological Evaluation of the First Novel Macrocycle-Based FGFR Inhibitors That Overcome Clinically Acquired Resistance.,Xiang S, Chen X, Lin J, Lin X, Lin Q, Song X, Yan L, Peng H, Tu Z, Patterson AV, Smaill JB, Tu Y, Chen Y, Lu X J Med Chem. 2026 Jan 22;69(2):1178-1198. doi: 10.1021/acs.jmedchem.5c02462. Epub , 2026 Jan 5. PMID:41490805<ref>PMID:41490805</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 9u7s" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Chen XJ]] | |||
[[Category: Chen YH]] | |||
Latest revision as of 13:27, 10 February 2026
FGFR2 kinase domain with a macrocyclic compound 8r
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