2yki: Difference between revisions

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-[[Image:2yki.png|left|200px]]
+==TRICYCLIC SERIES OF HSP90 INHIBITORS==
+<StructureSection load='2yki' size='340' side='right' caption='[[2yki]], [[Resolution|resolution]] 1.67&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[2yki]] is a 1 chain structure with 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=2YKI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2YKI FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=YKI:1-H-PYRROLO[2,3-B]PYRIDINE-4-CARBOXYLIC+ACID+[4-(3H-IMIDAZO[4,5-C]PYRIDIN-2-YL)-9H-FLUOREN-9-YL]-AMIDE'>YKI</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2yk9|2yk9]], [[2yi0|2yi0]], [[1osf|1osf]], [[2bsm|2bsm]], [[2wi3|2wi3]], [[2ye4|2ye4]], [[2yi5|2yi5]], [[2ye5|2ye5]], [[2bz5|2bz5]], [[2yei|2yei]], [[2ccs|2ccs]], [[2yeg|2yeg]], [[1yc3|1yc3]], [[1uyf|1uyf]], [[1uyi|1uyi]], [[2ye3|2ye3]], [[2byi|2byi]], [[2yi6|2yi6]], [[2vci|2vci]], [[2wi1|2wi1]], [[2xjx|2xjx]], [[2fwz|2fwz]], [[2xdk|2xdk]], [[1uyh|1uyh]], [[2xjg|2xjg]], [[2fwy|2fwy]], [[1uyl|1uyl]], [[1uye|1uye]], [[2xab|2xab]], [[2yeh|2yeh]], [[2xht|2xht]], [[2xhr|2xhr]], [[1uy7|1uy7]], [[2yef|2yef]], [[2byh|2byh]], [[2wi5|2wi5]], [[1yes|1yes]], [[1uy9|1uy9]], [[2cdd|2cdd]], [[1byq|1byq]], [[2yi7|2yi7]], [[1uy8|1uy8]], [[2bug|2bug]], [[2wi4|2wi4]], [[2yeb|2yeb]], [[2uwd|2uwd]], [[2ye7|2ye7]], [[2ykc|2ykc]], [[2wi7|2wi7]], [[2xhx|2xhx]], [[2bt0|2bt0]], [[2yej|2yej]], [[1yer|1yer]], [[2yec|2yec]], [[2xdu|2xdu]], [[1uyg|1uyg]], [[2ccu|2ccu]], [[2xds|2xds]], [[2xdx|2xdx]], [[2xk2|2xk2]], [[2xjj|2xjj]], [[1uyd|1uyd]], [[2xdl|2xdl]], [[2wi2|2wi2]], [[2yee|2yee]], [[1uy6|1uy6]], [[2ye2|2ye2]], [[2vcj|2vcj]], [[1yc4|1yc4]], [[2ye9|2ye9]], [[2c2l|2c2l]], [[1uyk|1uyk]], [[2cct|2cct]], [[2yk2|2yk2]], [[2wi6|2wi6]], [[2yea|2yea]], [[1yc1|1yc1]], [[2ye6|2ye6]], [[2yed|2yed]], [[1uyc|1uyc]], [[1yet|1yet]], [[2yjx|2yjx]], [[2jjc|2jjc]], [[2ye8|2ye8]], [[2ykb|2ykb]], [[2ykj|2ykj]]</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2yki FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2yki OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2yki RCSB], [http://www.ebi.ac.uk/pdbsum/2yki PDBsum]</span></td></tr>
+</table>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole- 6-one] (1) compound showed moderate activity (IC(50) = 7.6 muM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 A away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.
-{{STRUCTURE_2yki|  PDB=2yki  |  SCENE=  }}
+Tricyclic Series of Heat Shock Protein 90 (Hsp90) Inhibitors Part I: Discovery of Tricyclic Imidazo[4,5-c]pyridines as Potent Inhibitors of the Hsp90 Molecular Chaperone.,Vallee F, Carrez C, Pilorge F, Dupuy A, Parent A, Bertin L, Thompson F, Ferrari P, Fassy F, Lamberton A, Thomas A, Arrebola R, Guerif S, Rohaut A, Certal V, Ruxer JM, Delorme C, Jouanen A, Dumas J, Grepin C, Combeau C, Goulaouic H, Dereu N, Mikol V, Mailliet P, Minoux H J Med Chem. 2011 Oct 27;54(20):7206-19. Epub 2011 Oct 5. PMID:21972823<ref>PMID:21972823</ref>
-===TRICYCLIC SERIES OF HSP90 INHIBITORS===
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-{{ABSTRACT_PUBMED_21972823}}
+== References ==
+<references/>
-==About this Structure==
+__TOC__
-[[2yki]] is a 1 chain structure with 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=2YKI OCA].
+</StructureSection>
-==See Also==
-*[[Heat Shock Proteins|Heat Shock Proteins]]
-==Reference==
-<ref group="xtra">PMID:021972823</ref><references group="xtra"/>
 [[Category: Homo sapiens]]
 [[Category: Dupuy, A.]]