3qtf: Difference between revisions

Revision as of 01:32, 5 August 2016

Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity

Structural highlights

3qtf is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	05S, DMS
Gene:	HSP90A, HSP90AA1, HSPC1, HSPCA (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1] ^[2]

Publication Abstract from PubMed

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.

Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity.,Zapf CW, Bloom JD, McBean JL, Dushin RG, Nittoli T, Ingalls C, Sutherland AG, Sonye JP, Eid CN, Golas J, Liu H, Boschelli F, Hu Y, Vogan E, Levin JI Bioorg Med Chem Lett. 2011 Apr 15;21(8):2278-82. Epub 2011 Feb 28. PMID:21420297^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Martinez-Ruiz A, Villanueva L, Gonzalez de Orduna C, Lopez-Ferrer D, Higueras MA, Tarin C, Rodriguez-Crespo I, Vazquez J, Lamas S. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8525-30. Epub 2005 Jun 3. PMID:15937123 doi:10.1073/pnas.0407294102
↑ Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem. 2001 May 11;276(19):15571-4. Epub 2001 Mar 23. PMID:11274138 doi:10.1074/jbc.C100055200
↑ Zapf CW, Bloom JD, McBean JL, Dushin RG, Nittoli T, Ingalls C, Sutherland AG, Sonye JP, Eid CN, Golas J, Liu H, Boschelli F, Hu Y, Vogan E, Levin JI. Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity. Bioorg Med Chem Lett. 2011 Apr 15;21(8):2278-82. Epub 2011 Feb 28. PMID:21420297 doi:10.1016/j.bmcl.2011.02.101

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OCA

[1] Martinez-Ruiz A, Villanueva L, Gonzalez de Orduna C, Lopez-Ferrer D, Higueras MA, Tarin C, Rodriguez-Crespo I, Vazquez J, Lamas S. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8525-30. Epub 2005 Jun 3. PMID:15937123 doi:10.1073/pnas.0407294102

[2] Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem. 2001 May 11;276(19):15571-4. Epub 2001 Mar 23. PMID:11274138 doi:10.1074/jbc.C100055200

[3] Zapf CW, Bloom JD, McBean JL, Dushin RG, Nittoli T, Ingalls C, Sutherland AG, Sonye JP, Eid CN, Golas J, Liu H, Boschelli F, Hu Y, Vogan E, Levin JI. Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity. Bioorg Med Chem Lett. 2011 Apr 15;21(8):2278-82. Epub 2011 Feb 28. PMID:21420297 doi:10.1016/j.bmcl.2011.02.101

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
 ==Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity==
 <StructureSection load='3qtf' size='340' side='right' caption='[[3qtf]], [[Resolution|resolution]] 1.57&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3qtf]] 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=3QTF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QTF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3qtf]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3QTF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3QTF FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=05S:(6S)-6,15,15,18-TETRAMETHYL-17-OXO-2,3,4,5,6,7,14,15,16,17-DECAHYDRO-1H-8,12-(METHENO)[1,4,9]TRIAZACYCLOTETRADECINO[9,8-A]INDOLE-9-CARBOXAMIDE'>05S</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></td></tr>
-<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>
+<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 HUMAN])</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=3qtf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qtf OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3qtf RCSB], [http://www.ebi.ac.uk/pdbsum/3qtf PDBsum]</span></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=3qtf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3qtf OCA], [http://pdbe.org/3qtf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3qtf RCSB], [http://www.ebi.ac.uk/pdbsum/3qtf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3qtf ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3qtf" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 24: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Bloom, J D]]
 [[Category: Boschelli, F]]

3qtf: Difference between revisions

Revision as of 01:32, 5 August 2016

Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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