PDBsum entry 2wi3

Chaperone

PDB id: 2wi3

Contents

Protein chain

209 a.a. *

Ligands

ZZ3

Metals

_MG

Waters ×271

* Residue conservation analysis

PDB id:

2wi3

Name:

Chaperone

Title:

Orally active 2-amino thienopyrimidine inhibitors of the hsp90 chaperone

Structure:

Heat shock protein, hsp 90-alpha. Chain: a. Fragment: n-terminal atp-binding domain, residues 1-236. Synonym: hsp 86, renal carcinoma antigen ny-ren-38. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Organ: skin. Tissue: melanoma. Expressed in: escherichia coli. Expression_system_taxid: 469008. Other_details: cloned from image\:4026275

Resolution:

1.90Å R-factor: 0.200 R-free: 0.242

Authors:

P.A.Brough,X.Barril,J.Borgognoni,P.Chene,N.G.M.Davies,B.Davis, M.J.Drysdale,B.Dymock,S.A.Eccles,C.Garcia-Echeverria,C.Fromont, A.Hayes,R.E.Hubbard,A.M.Jordan,M.Rugaard-Jensen,A.Massey,A.Merret, A.Padfield,R.Parsons,T.Radimerski,F.I.Raynaud,A.Robertson, S.D.Roughley,J.Schoepfer,H.Simmonite,A.Surgenor,M.Valenti,S.Walls, P.Webb,M.Wood,P.Workman,L.M.Wright

Key ref:

P.A.Brough et al. (2009). 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, 52, 4794-4809. PubMed id: 19610616

Date:

08-May-09 Release date: 28-Jul-09

Protein chain

P07900  (HS90A_HUMAN) -  Heat shock protein HSP 90-alpha from Homo sapiens

Seq: 732 a.a.

Struc: 209 a.a.

Enzyme reactions

• Enzyme class: E.C.3.6.4.10 - non-chaperonin molecular chaperone ATPase.
• Reaction: ATP + H2O = ADP + phosphate + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

J Med Chem 52:4794-4809 (2009)

PubMed id: 19610616

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.

P.A.Brough, X.Barril, J.Borgognoni, P.Chene, N.G.Davies, B.Davis, M.J.Drysdale, B.Dymock, S.A.Eccles, C.Garcia-Echeverria, C.Fromont, A.Hayes, R.E.Hubbard, A.M.Jordan, M.R.Jensen, A.Massey, A.Merrett, A.Padfield, R.Parsons, T.Radimerski, F.I.Raynaud, A.Robertson, S.D.Roughley, J.Schoepfer, H.Simmonite, S.Y.Sharp, A.Surgenor, M.Valenti, S.Walls, P.Webb, M.Wood, P.Workman, L.Wright.

ABSTRACT

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 (IC50 = 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.