3c4f: Difference between revisions
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New page: left|200px<br /><applet load="3c4f" size="350" color="white" frame="true" align="right" spinBox="true" caption="3c4f, resolution 2.07Å" /> '''FGFR TYROSINE KINASE... |
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[[Image:3c4f.jpg|left|200px]] | [[Image:3c4f.jpg|left|200px]] | ||
'''FGFR TYROSINE KINASE DOMAIN IN COMPLEX WITH 3-(3-methoxybenzyl)-7-azaindole''' | {{Structure | ||
|PDB= 3c4f |SIZE=350|CAPTION= <scene name='initialview01'>3c4f</scene>, resolution 2.07Å | |||
|SITE= <scene name='pdbsite=AC1:C4f+Binding+Site+For+Residue+A+1'>AC1</scene> and <scene name='pdbsite=AC2:C4f+Binding+Site+For+Residue+B+2'>AC2</scene> | |||
|LIGAND= <scene name='pdbligand=C4F:'>C4F</scene> | |||
|ACTIVITY= [http://en.wikipedia.org/wiki/Receptor_protein-tyrosine_kinase Receptor protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 2.7.10.1] | |||
|GENE= FGFR1, FGFBR, FLG, FLT2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]) | |||
}} | |||
'''FGFR TYROSINE KINASE DOMAIN IN COMPLEX WITH 3-(3-methoxybenzyl)-7-azaindole''' | |||
==Overview== | |||
BRAF(V600E) is the most frequent oncogenic protein kinase mutation known. Furthermore, inhibitors targeting "active" protein kinases have demonstrated significant utility in the therapeutic repertoire against cancer. Therefore, we pursued the development of specific kinase inhibitors targeting B-Raf, and the V600E allele in particular. By using a structure-guided discovery approach, a potent and selective inhibitor of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E) kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele. Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-Raf(V600E)-bearing tumor cell lines but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and apoptosis exclusively in B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. The work described here represents the entire discovery process, from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B-Raf(V600E)-driven tumors. | |||
==About this Structure== | ==About this Structure== | ||
3C4F is a [ | 3C4F is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3C4F OCA]. | ||
==Reference== | |||
Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity., Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G, Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6. Epub 2008 Feb 19. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18287029 18287029] | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Receptor protein-tyrosine kinase]] | [[Category: Receptor protein-tyrosine kinase]] | ||
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[[Category: tyrosine-protein kinase]] | [[Category: tyrosine-protein kinase]] | ||
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 19:02:28 2008'' | ||
