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J Med Chem. 2010 Aug 26;53(16):5956-69. doi: 10.1021/jm100060b.

Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.

Author information

1
Medicinal Chemistry, Astex Therapeutics, Ltd., Cambridge, UK. a.woodhead@astex-therapeutics.com

Abstract

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.

PMID:
20662534
DOI:
10.1021/jm100060b
[Indexed for MEDLINE]

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