6v9c: Difference between revisions
Jump to navigation
Jump to search
New page: '''Unreleased structure''' The entry 6v9c is ON HOLD Authors: Liu, J., Liu, H. Description: Crystal structure of FGFR4 kinase domain in complex with covalent inhibitor [[Category: Unre... |
No edit summary |
||
| (4 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Crystal structure of FGFR4 kinase domain in complex with covalent inhibitor== | |||
<StructureSection load='6v9c' size='340' side='right'caption='[[6v9c]], [[Resolution|resolution]] 1.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6v9c]] 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=6V9C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6V9C 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]] 1.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QS7:~{N}-[(3~{R},4~{S})-4-[[6-[2,6-bis(chloranyl)-3,5-dimethoxy-phenyl]-8-methyl-7-oxidanylidene-pyrido[2,3-d]pyrimidin-2-yl]amino]oxolan-3-yl]prop-2-enamide'>QS7</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=6v9c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6v9c OCA], [https://pdbe.org/6v9c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6v9c RCSB], [https://www.ebi.ac.uk/pdbsum/6v9c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6v9c ProSAT]</span></td></tr> | |||
</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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Hepatocellular carcinoma (HCC) accounts for a majority of primary liver cancer and is one of the most common forms of cancer worldwide. Aberrant signaling of the FGF19-FGFR4 pathway leads to HCC in mice and is hypothesized to be a driver in FGF19 amplified HCC in humans. Multiple small molecule inhibitors have been pursued as targeted therapies for HCC in recent years, including several selective FGFR4 inhibitors that are currently being evaluated in clinical trials. Herein, we report a novel series of highly selective, covalent 2-amino-6,8-dimethyl-pyrido[2,3-d]pyrimidin-7(8H)-ones that potently and selectively inhibit FGFR4 signaling through covalent modification of Cys552, which was confirmed by X-ray crystallography. Correlative target occupancy and pFGFR4 inhibition were observed in vivo, as well as tumor regression in preclinical models of orthotopic and sorafenib-resistant HCC. | |||
Discovery of Selective, Covalent FGFR4 Inhibitors with Antitumor Activity in Models of Hepatocellular Carcinoma.,Liu H, Niu D, Tham Sjin RT, Dubrovskiy A, Zhu Z, McDonald JJ, Fahnoe K, Wang Z, Munson M, Scholte A, Barrague M, Fitzgerald M, Liu J, Kothe M, Sun F, Murtie J, Ge J, Rocnik J, Harvey D, Ospina B, Perron K, Zheng G, Shehu E, D'Agostino LA ACS Med Chem Lett. 2020 Mar 6;11(10):1899-1904. doi:, 10.1021/acsmedchemlett.9b00601. eCollection 2020 Oct 8. PMID:33062171<ref>PMID:33062171</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Liu | <div class="pdbe-citations 6v9c" style="background-color:#fffaf0;"></div> | ||
[[Category: Liu | |||
==See Also== | |||
*[[Fibroblast growth factor receptor 3D receptor|Fibroblast growth factor receptor 3D receptor]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Liu H]] | |||
[[Category: Liu J]] | |||
Latest revision as of 08:52, 21 November 2024
Crystal structure of FGFR4 kinase domain in complex with covalent inhibitorCrystal structure of FGFR4 kinase domain in complex with covalent inhibitor
Structural highlights
FunctionFGFR4_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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] Publication Abstract from PubMedHepatocellular carcinoma (HCC) accounts for a majority of primary liver cancer and is one of the most common forms of cancer worldwide. Aberrant signaling of the FGF19-FGFR4 pathway leads to HCC in mice and is hypothesized to be a driver in FGF19 amplified HCC in humans. Multiple small molecule inhibitors have been pursued as targeted therapies for HCC in recent years, including several selective FGFR4 inhibitors that are currently being evaluated in clinical trials. Herein, we report a novel series of highly selective, covalent 2-amino-6,8-dimethyl-pyrido[2,3-d]pyrimidin-7(8H)-ones that potently and selectively inhibit FGFR4 signaling through covalent modification of Cys552, which was confirmed by X-ray crystallography. Correlative target occupancy and pFGFR4 inhibition were observed in vivo, as well as tumor regression in preclinical models of orthotopic and sorafenib-resistant HCC. Discovery of Selective, Covalent FGFR4 Inhibitors with Antitumor Activity in Models of Hepatocellular Carcinoma.,Liu H, Niu D, Tham Sjin RT, Dubrovskiy A, Zhu Z, McDonald JJ, Fahnoe K, Wang Z, Munson M, Scholte A, Barrague M, Fitzgerald M, Liu J, Kothe M, Sun F, Murtie J, Ge J, Rocnik J, Harvey D, Ospina B, Perron K, Zheng G, Shehu E, D'Agostino LA ACS Med Chem Lett. 2020 Mar 6;11(10):1899-1904. doi:, 10.1021/acsmedchemlett.9b00601. eCollection 2020 Oct 8. PMID:33062171[15] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||