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

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.; O’Brien, M. Alistair; Parra, Lina; Patel, Sahil; Phillips, Theresa; Rees, David C.; Rich, Sharna; Smith, Donna-Michelle; Trewartha, Gary; Vinkovic, Mladen; Williams, Brian; Woolford, Alison J.-A.

doi:10.1021/jm100060b.s001

jm100060b_si_001.pdf (315.37 kB)

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

journal contribution

posted on 2010-08-26, 00:00 authored by 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, Martyn Frederickson, Jonathan Lewis, Rachel McMenamin, Christopher W. Murray, M. Alistair O’Brien, Lina Parra, Sahil Patel, Theresa Phillips, David C. Rees, Sharna Rich, Donna-Michelle Smith, Gary Trewartha, Mladen Vinkovic, Brian Williams, Alison J.-A. Woolford

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.