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.

中文翻译：

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发现（2,4-Dihydroxy-5-isopropylphenyl）-[5-（4-methylpiperazin-1-ylmethyl）-1,3-dihydroisoindol-2-yl] methanone（AT13387），新型分子伴侣Hsp90抑制剂基于片段的药物设计

分子伴侣热休克蛋白90（Hsp90）的抑制剂目前正作为一种潜在的癌症治疗方法，在临床开发中引起极大的兴趣。在先前的出版物（DOI：10.1021 / jm100059d）中，我们描述了Astex筛选针对Hsp90的片段的方法，以及随后将两个命中的优化为具有低纳摩尔范围内抑制活性的先导物的方法。本文描述了2,4-二羟基苯甲酰胺前导分子1的结构导向优化，并详细介绍了用于鉴定AT13387（35）的一些药物发现策略，该策略已通过临床前开发进行了开发，目前正在人体中进行测试。