Literature

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.

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

Journal of Medicinal Chemistry 2010.0

Identification of a new series of potent diphenol HSP90 inhibitors by fragment merging and structure-based optimization

Bioorganic & Medicinal Chemistry Letters 2014.0

Lead generation of heat shock protein 90 inhibitors by a combination of fragment-based approach, virtual screening, and structure-based drug design

Bioorganic & Medicinal Chemistry Letters 2011.0

Discovery of Benzisoxazoles as Potent Inhibitors of Chaperone Heat Shock Protein 90

Journal of Medicinal Chemistry 2008.0

Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone

Journal of Medicinal Chemistry 2009.0

Novel, Potent Small-Molecule Inhibitors of the Molecular Chaperone Hsp90 Discovered through Structure-Based Design