2xab

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2xab, resolution 1.90Å ()
Ligands:
Related: 2cdd, 1yes, 1uy9, 1byq, 2bsm, 1osf, 2wi3, 1uy8, 2bug, 2wi4, 2uwd, 2wi7, 2bt0, 1yer, 1uyg, 2bz5, 2ccu, 2ccs, 1uyi, 1yc3, 1uyf, 1uyd, 2byi, 2wi2, 1uy6, 2vci, 2wi1, 2vcj, 1yc4, 2fwz, 2c2l, 1uyk, 1uyh, 2cct, 2fwy, 1uye, 1uyl, 2wi6, 1yc1, 1uyc, 1uy7, 1yet, 2jjc, 2byh, 2wi5


Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



Contents

STRUCTURE OF HSP90 WITH AN INHIBITOR BOUND

Publication Abstract from PubMed

Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.

Discovery of (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-di hydroisoindol-2-yl]methanone (AT13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design., Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ, J Med Chem. 2010 Jul 28. PMID:20662534

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

About this Structure

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

See Also

Reference

  • Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, Woolford AJ. Discovery of (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-di hydroisoindol-2-yl]methanone (AT13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design. J Med Chem. 2010 Jul 28. PMID:20662534 doi:10.1021/jm100060b
  • Murray CW, Carr MG, Callaghan O, Chessari G, Congreve M, Cowan S, Coyle JE, Downham R, Figueroa E, Frederickson M, Graham B, McMenamin R, O'Brien MA, Patel S, Phillips TR, Williams G, Woodhead AJ, Woolford AJ. Fragment-based drug discovery applied to hsp90. Discovery of two lead series with high ligand efficiency. J Med Chem. 2010 Aug 26;53(16):5942-55. PMID:20718493 doi:10.1021/jm100059d

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