3r91

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==Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.==
==Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.==
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<StructureSection load='3r91' size='340' side='right' caption='[[3r91]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
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<StructureSection load='3r91' size='340' side='right'caption='[[3r91]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[3r91]] 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=3R91 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3R91 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[3r91]] 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=3R91 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3R91 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=06H:(6S)-4,6,15,15,18-PENTAMETHYL-5,17-DIOXO-2,3,4,5,6,7,14,15,16,17-DECAHYDRO-1H-12,8-(METHENO)[1,4,9]TRIAZACYCLOTETRADECINO[9,8-A]INDOLE-9-CARBOXAMIDE'>06H</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.579&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90A, HSP90AA1, HSPC1, HSPCA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=06H:(6S)-4,6,15,15,18-PENTAMETHYL-5,17-DIOXO-2,3,4,5,6,7,14,15,16,17-DECAHYDRO-1H-12,8-(METHENO)[1,4,9]TRIAZACYCLOTETRADECINO[9,8-A]INDOLE-9-CARBOXAMIDE'>06H</scene></td></tr>
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<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=3r91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3r91 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3r91 RCSB], [http://www.ebi.ac.uk/pdbsum/3r91 PDBsum]</span></td></tr>
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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=3r91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3r91 OCA], [https://pdbe.org/3r91 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3r91 RCSB], [https://www.ebi.ac.uk/pdbsum/3r91 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3r91 ProSAT]</span></td></tr>
</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/HS90A_HUMAN HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.<ref>PMID:15937123</ref> <ref>PMID:11274138</ref>
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A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24h post-administration, consistent with elevated and prolonged exposure in the tumor.
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Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.,Zapf CW, Bloom JD, McBean JL, Dushin RG, Nittoli T, Otteng M, Ingalls C, Golas JM, Liu H, Lucas J, Boschelli F, Hu Y, Vogan E, Levin JI Bioorg Med Chem Lett. 2011 Apr 5. PMID:21515049<ref>PMID:21515049</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==See Also==
==See Also==
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*[[Heat Shock Proteins|Heat Shock Proteins]]
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*[[Heat Shock Protein structures|Heat Shock Protein structures]]
== References ==
== References ==
<references/>
<references/>
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</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Bloom, J D]]
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[[Category: Large Structures]]
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[[Category: Boschelli, F]]
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[[Category: Bloom JD]]
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[[Category: Dushin, R G]]
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[[Category: Boschelli F]]
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[[Category: Golas, J M]]
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[[Category: Dushin RG]]
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[[Category: Hu, Y]]
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[[Category: Golas JM]]
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[[Category: Ingalls, C]]
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[[Category: Hu Y]]
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[[Category: Levin, J I]]
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[[Category: Ingalls C]]
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[[Category: Liu, H]]
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[[Category: Levin JI]]
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[[Category: Lucas, J]]
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[[Category: Liu H]]
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[[Category: McBean, J L]]
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[[Category: Lucas J]]
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[[Category: Nittoli, T]]
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[[Category: McBean JL]]
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[[Category: Otteng, M]]
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[[Category: Nittoli T]]
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[[Category: Vogan, E]]
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[[Category: Otteng M]]
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[[Category: Zapf, C W]]
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[[Category: Vogan E]]
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[[Category: Atp binding domain]]
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[[Category: Zapf CW]]
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[[Category: Atp-binding]]
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[[Category: Chaperone]]
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[[Category: Chaperone-chaperone inhibitor complex]]
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[[Category: Nucleotide-binding]]
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[[Category: Phosphoprotein]]
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[[Category: Stress response]]
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Current revision

Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.

PDB ID 3r91

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OCA

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