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[[Image:2wi2.png|left|200px]]


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==Orally Active 2-Amino Thienopyrimidine Inhibitors of the Hsp90 Chaperone==
The line below this paragraph, containing "STRUCTURE_2wi2", creates the "Structure Box" on the page.
<StructureSection load='2wi2' size='340' side='right'caption='[[2wi2]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
You may change the PDB parameter (which sets the PDB file loaded into the applet)
== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[2wi2]] is a 2 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=2WI2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2WI2 FirstGlance]. <br>
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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]] 2.09&#8491;</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=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=ZZ3:4-METHYL-6-(METHYLSULFANYL)-1,3,5-TRIAZIN-2-AMINE'>ZZ3</scene></td></tr>
{{STRUCTURE_2wi2|  PDB=2wi2  |  SCENE=  }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2wi2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wi2 OCA], [https://pdbe.org/2wi2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2wi2 RCSB], [https://www.ebi.ac.uk/pdbsum/2wi2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2wi2 ProSAT]</span></td></tr>
</table>
== Function ==
[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>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wi/2wi2_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2wi2 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC(50) = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.


===ORALLY ACTIVE 2-AMINO THIENOPYRIMIDINE INHIBITORS OF THE HSP90 CHAPERONE===
Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone.,Brough PA, Barril X, Borgognoni J, Chene P, Davies NG, Davis B, Drysdale MJ, Dymock B, Eccles SA, Garcia-Echeverria C, Fromont C, Hayes A, Hubbard RE, Jordan AM, Jensen MR, Massey A, Merrett A, Padfield A, Parsons R, Radimerski T, Raynaud FI, Robertson A, Roughley SD, Schoepfer J, Simmonite H, Sharp SY, Surgenor A, Valenti M, Walls S, Webb P, Wood M, Workman P, Wright L J Med Chem. 2009 Jul 17. PMID:19610616<ref>PMID:19610616</ref>


 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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{{ABSTRACT_PUBMED_19610616}}
 
==About this Structure==
[[2wi2]] is a 2 chain structure of [[Heat Shock Proteins]] 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=2WI2 OCA].


==See Also==
==See Also==
*[[Heat Shock Proteins]]
*[[Heat Shock Protein structures|Heat Shock Protein structures]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:19610616</ref><references group="xtra"/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Barril, X.]]
[[Category: Large Structures]]
[[Category: Borgognoni, J.]]
[[Category: Barril X]]
[[Category: Brough, P A.]]
[[Category: Borgognoni J]]
[[Category: Chene, P.]]
[[Category: Brough PA]]
[[Category: Davies, N G.M.]]
[[Category: Chene P]]
[[Category: Davis, B.]]
[[Category: Davies NGM]]
[[Category: Drysdale, M J.]]
[[Category: Davis B]]
[[Category: Dymock, B.]]
[[Category: Drysdale MJ]]
[[Category: Eccles, S A.]]
[[Category: Dymock B]]
[[Category: Fromont, C.]]
[[Category: Eccles SA]]
[[Category: Garcia-Echeverria, C.]]
[[Category: Fromont C]]
[[Category: Hayes, A.]]
[[Category: Garcia-Echeverria C]]
[[Category: Hubbard, R E.]]
[[Category: Hayes A]]
[[Category: Jordan, A M.]]
[[Category: Hubbard RE]]
[[Category: Massey, A.]]
[[Category: Jordan AM]]
[[Category: Merret, A.]]
[[Category: Massey A]]
[[Category: Padfield, A.]]
[[Category: Merret A]]
[[Category: Parsons, R.]]
[[Category: Padfield A]]
[[Category: Radimerski, T.]]
[[Category: Parsons R]]
[[Category: Raynaud, F I.]]
[[Category: Radimerski T]]
[[Category: Robertson, A.]]
[[Category: Raynaud FI]]
[[Category: Roughley, S D.]]
[[Category: Robertson A]]
[[Category: Rugaard-Jensen, M.]]
[[Category: Roughley SD]]
[[Category: Schoepfer, J.]]
[[Category: Rugaard-Jensen M]]
[[Category: Simmonite, H.]]
[[Category: Schoepfer J]]
[[Category: Surgenor, A.]]
[[Category: Simmonite H]]
[[Category: Valenti, M.]]
[[Category: Surgenor A]]
[[Category: Walls, S.]]
[[Category: Valenti M]]
[[Category: Webb, P.]]
[[Category: Walls S]]
[[Category: Wood, M.]]
[[Category: Webb P]]
[[Category: Workman, P.]]
[[Category: Wood M]]
[[Category: Wright, L M.]]
[[Category: Workman P]]
[[Category: Alternative splicing]]
[[Category: Wright LM]]
[[Category: Atp-binding]]
[[Category: Atpase]]
[[Category: Chaperone]]
[[Category: Cytoplasm]]
[[Category: Heat shock]]
[[Category: Hsp90]]
[[Category: Nucleotide-binding]]
[[Category: Phosphoprotein]]
[[Category: Phosphorylation]]
[[Category: Pu3]]
[[Category: Stress response]]

Latest revision as of 18:57, 13 December 2023

Orally Active 2-Amino Thienopyrimidine Inhibitors of the Hsp90 ChaperoneOrally Active 2-Amino Thienopyrimidine Inhibitors of the Hsp90 Chaperone

Structural highlights

2wi2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.09Å
Ligands:,
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]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC(50) = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.

Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone.,Brough PA, Barril X, Borgognoni J, Chene P, Davies NG, Davis B, Drysdale MJ, Dymock B, Eccles SA, Garcia-Echeverria C, Fromont C, Hayes A, Hubbard RE, Jordan AM, Jensen MR, Massey A, Merrett A, Padfield A, Parsons R, Radimerski T, Raynaud FI, Robertson A, Roughley SD, Schoepfer J, Simmonite H, Sharp SY, Surgenor A, Valenti M, Walls S, Webb P, Wood M, Workman P, Wright L J Med Chem. 2009 Jul 17. PMID:19610616[3]

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

See Also

References

  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. ↑ Brough PA, Barril X, Borgognoni J, Chene P, Davies NG, Davis B, Drysdale MJ, Dymock B, Eccles SA, Garcia-Echeverria C, Fromont C, Hayes A, Hubbard RE, Jordan AM, Jensen MR, Massey A, Merrett A, Padfield A, Parsons R, Radimerski T, Raynaud FI, Robertson A, Roughley SD, Schoepfer J, Simmonite H, Sharp SY, Surgenor A, Valenti M, Walls S, Webb P, Wood M, Workman P, Wright L. Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone. J Med Chem. 2009 Jul 17. PMID:19610616 doi:10.1021/jm900357y

2wi2, resolution 2.09Å

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