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
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- 作者：Andrew J. Woodhead ; Hayley Angove ; Maria G. Carr ; Gianni Chessari ; Miles Congreve ; Joseph E. Coyle ; Jose Cosme ; Brent Graham ; Philip J. Day ; Robert Downham ; Lynsey Fazal ; Ruth Feltell ; Eva Figueroa ; M
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：August 26, 2010
- 年：2010
- 卷：53
- 期：16
- 页码：5956-5969
- 全文大小：1254K
- 年卷期：v.53,no.16(August 26, 2010)
- ISSN：1520-4804
文摘
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.