7ybp
From Proteopedia
(Difference between revisions)
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<table><tr><td colspan='2'>[[7ybp]] 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=7YBP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7YBP FirstGlance]. <br> | <table><tr><td colspan='2'>[[7ybp]] 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=7YBP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7YBP 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]] 2.243Å</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]] 2.243Å</td></tr> | ||
- | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IH7:~{N}-[4-[ | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=IH7:~{N}-[4-[1-[3,5-bis(chloranyl)pyridin-4-yl]ethoxy]-5-cyano-pyridin-2-yl]-6-bromanyl-5-methanoyl-1-(2-morpholin-4-ylethyl)pyrrolo[3,2-b]pyridine-3-carboxamide'>IH7</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=7ybp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ybp OCA], [https://pdbe.org/7ybp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ybp RCSB], [https://www.ebi.ac.uk/pdbsum/7ybp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ybp 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=7ybp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ybp OCA], [https://pdbe.org/7ybp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ybp RCSB], [https://www.ebi.ac.uk/pdbsum/7ybp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ybp ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
- | The FGF19-FGFR4 signaling pathway has been extensively studied as a promising target for the treatment of hepatocellular carcinoma (HCC). Several FGFR4-selective inhibitors have been developed, but none of them receives approval. Additionally, acquired resistance caused by FGFR4 gatekeeper mutations is emerging as a serious limitation for these targeted therapies. Herein, we report a novel series of 5-formyl-pyrrolo[3,2-b]pyridine derivatives as new reversible-covalent inhibitors targeting wild-type and gatekeeper mutant variants of FGFR4 kinase. The representative compound 10z exhibited single-digit nanomolar activity against wild-type FGFR4 and the FGFR4(V550L/M) mutant variants in biochemical and Ba/F3 cellular assays, while sparing FGFR1/2/3. Furthermore, 10z showed significant antiproliferative activity against Hep3B, JHH-7, and HuH-7 HCC cells with | + | The FGF19-FGFR4 signaling pathway has been extensively studied as a promising target for the treatment of hepatocellular carcinoma (HCC). Several FGFR4-selective inhibitors have been developed, but none of them receives approval. Additionally, acquired resistance caused by FGFR4 gatekeeper mutations is emerging as a serious limitation for these targeted therapies. Herein, we report a novel series of 5-formyl-pyrrolo[3,2-b]pyridine derivatives as new reversible-covalent inhibitors targeting wild-type and gatekeeper mutant variants of FGFR4 kinase. The representative compound 10z exhibited single-digit nanomolar activity against wild-type FGFR4 and the FGFR4(V550L/M) mutant variants in biochemical and Ba/F3 cellular assays, while sparing FGFR1/2/3. Furthermore, 10z showed significant antiproliferative activity against Hep3B, JHH-7, and HuH-7 HCC cells with IC(50) values of 37, 32, and 94 nM, respectively. MALDI-TOF-MS and X-ray protein crystallography studies were consistent with 10z acting as a reversible-covalent inhibitor of FGFR4, serving as a promising lead compound for further anticancer drug development. |
- | Design, Synthesis, and Biological Evaluation of 5-Formyl-pyrrolo[3,2-b]pyridine-3-carboxamides as New Selective, Potent, and Reversible-Covalent FGFR4 Inhibitors.,Yang F, Chen X, Song X, Ortega R, Lin X, Deng W, Guo J, Tu Z, Patterson AV, Smaill JB, Chen Y, Lu X J Med Chem. 2022 Nov 10;65(21):14809-14831. doi: 10.1021/acs.jmedchem.2c01319., Epub 2022 Oct 24. PMID:36278929<ref>PMID:36278929</ref> | + | Design, Synthesis, and Biological Evaluation of 5-Formyl-pyrrolo[3,2-b]pyridine-3-carboxamides as New Selective, Potent, and Reversible-Covalent FGFR4 Inhibitors.,Yang F, Chen X, Song X, Ortega R, Lin X, Deng W, Guo J, Tu Z, Patterson AV, Smaill JB, Chen Y, Lu X J Med Chem. 2022 Nov 10;65(21):14809-14831. doi: 10.1021/acs.jmedchem.2c01319. , Epub 2022 Oct 24. PMID:36278929<ref>PMID:36278929</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
Current revision
Crystal structure of FGFR4(V550L) kinase domain with 10z
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