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

被引：222

作者：

Woodhead, Andrew J. ^{[1
]}

Angove, Hayley ^{[2
]}

Carr, Maria G. ^{[1
]}

Chessari, Gianni ^{[3
]}

Congreve, Miles ^{[1
]}

Coyle, Joseph E. ^{[2
]}

Cosme, Jose ^{[4
]}

Graham, Brent ^{[5
]}

Day, Philip J. ^{[6
]}

Downham, Robert ^{[1
]}

Fazal, Lynsey ^{[4
]}

Feltell, Ruth ^{[5
]}

Figueroa, Eva ^{[1
]}

Frederickson, Martyn ^{[1
]}

Lewis, Jonathan ^{[4
]}

McMenamin, Rachel ^{[5
]}

Murray, Christopher W. ^{[3
]}

O'Brien, M. Alistair ^{[1
]}

Parra, Lina ^{[4
]}

Patel, Sahil ^{[6
]}

Phillips, Theresa ^{[1
]}

Rees, David C. ^{[1
]}

Rich, Sharna ^{[5
]}

Smith, Donna-Michelle ^{[4
]}

Trewartha, Gary ^{[1
]}

Vinkovic, Mladen ^{[6
]}

Williams, Brian ^{[1
]}

Woolford, Alison J. -A. ^{[1
]}

机构：

[1] Astex Therapeut Ltd, Med Chem, Cambridge CB4 0QA, England

[2] Astex Therapeut Ltd, Biophys, Cambridge CB4 0QA, England

[3] Astex Therapeut Ltd, Computat Chem & Informat, Cambridge CB4 0QA, England

[4] Astex Therapeut Ltd, DMPK, Cambridge CB4 0QA, England

[5] Astex Therapeut Ltd, Biol, Cambridge CB4 0QA, England

[6] Astex Therapeut Ltd, Struct Biol, Cambridge CB4 0QA, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 16期

关键词：

SHOCK-PROTEIN; 90; BIOLOGICAL EVALUATION; RECEPTOR ANTAGONISTS; TUMOR SELECTIVITY; POTENT; HERG; PHARMACOKINETICS; BINDING; TARGET; IDENTIFICATION;

D O I：

10.1021/jm100060b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

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.

引用

页码：5956 / 5969

页数：14

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