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2wi2

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2wi2, resolution 2.09Å ()
Ligands: ,
Related: 2cdd, 1yes, 1uy9, 1byq, 1osf, 2bsm, 1uy8, 2bug, 2uwd, 2bt0, 1yer, 1uyg, 2bz5, 2ccu, 2ccs, 1uyi, 1yc3, 1uyf, 1uyd, 2byi, 1uy6, 2vci, 2vcj, 1yc4, 2c2l, 1uyk, 1uyh, 2cct, 1uye, 1uyl, 1yc1, 1uy7, 1uyc, 1yet, 2jjc, 2byh, 2wi4, 2wi7, 2wi6, 2wi3, 2wi1, 2wi5
Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



Contents

ORALLY ACTIVE 2-AMINO THIENOPYRIMIDINE INHIBITORS OF THE HSP90 CHAPERONE

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

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

About this Structure

2wi2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • 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

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