7yc1: Difference between revisions

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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7yc1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7yc1 OCA], [https://pdbe.org/7yc1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7yc1 RCSB], [https://www.ebi.ac.uk/pdbsum/7yc1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7yc1 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=7yc1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7yc1 OCA], [https://pdbe.org/7yc1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7yc1 RCSB], [https://www.ebi.ac.uk/pdbsum/7yc1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7yc1 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
[https://www.uniprot.org/uniprot/FGFR4_HUMAN FGFR4_HUMAN] Tyrosine-protein kinase that acts as cell-surface receptor for fibroblast growth factors and plays a role in the regulation of cell proliferation, differentiation and migration, and in regulation of lipid metabolism, bile acid biosynthesis, glucose uptake, vitamin D metabolism and phosphate homeostasis. Required for normal down-regulation of the expression of CYP7A1, the rate-limiting enzyme in bile acid synthesis, in response to FGF19. Phosphorylates PLCG1 and FRS2. Ligand binding leads to the activation of several signaling cascades. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. Phosphorylation of FRS2 triggers recruitment of GRB2, GAB1, PIK3R1 and SOS1, and mediates activation of RAS, MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling pathway, as well as of the AKT1 signaling pathway. Promotes SRC-dependent phosphorylation of the matrix protease MMP14 and its lysosomal degradation. FGFR4 signaling is down-regulated by receptor internalization and degradation; MMP14 promotes internalization and degradation of FGFR4. Mutations that lead to constitutive kinase activation or impair normal FGFR4 inactivation lead to aberrant signaling.<ref>PMID:7680645</ref> <ref>PMID:7518429</ref> <ref>PMID:8663044</ref> <ref>PMID:11433297</ref> <ref>PMID:16597617</ref> <ref>PMID:17623664</ref> <ref>PMID:17311277</ref> <ref>PMID:18480409</ref> <ref>PMID:18670643</ref> <ref>PMID:20683963</ref> <ref>PMID:20018895</ref> <ref>PMID:20798051</ref> <ref>PMID:21653700</ref> <ref>PMID:20876804</ref>
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== 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 IC50 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.
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&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Latest revision as of 09:22, 17 October 2024

Crystal structure of FGFR4 kinase domain with 10d

7yc1, resolution 2.54Å

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