【文章名】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
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
作者
WOODHEAD ANDREW J; ANGOVE HAYLEY; CARR MARIA G; CHESSARI GIANNI; CONGREVE MILES; COYLE JOSEPH E; COSME JOSE; GRAHAM BRENT; DAY PHILIP J; DOWNHAM ROBERT; FAZAL LYNSEY; FELTELL RUTH; FIGUEROA EVA; FREDERICKSON MARTYN; LEWIS JONATHAN; MCMENAMIN RACHEL; MURRAY CHRISTOPHER W; OBRIEN M ALISTAIR; PARRA LINA; PATEL SAHIL; PHILLIPS THERESA; REES DAVID C; RICH SHARNA; SMITH DONNAMICHELLE; TREWARTHA GARY; VINKOVIC MLADEN; WILLIAMS BRIAN; WOOLFORD ALISON J A
[摘要]：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.
