Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors
Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors
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DOI：
10.1016/j.bmc.2014.05.056
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发表时间：
2014-08-01
影响因子：
3.5
通讯作者：
Casuscelli, Francesco
中科院分区：
文献类型：
--
作者：
Casale, Elena;Amboldi, Nadia;Casuscelli, Francesco
在过去的十年中，热休克蛋白90（Hsp 90）已成为一个主要的治疗靶点，许多人致力于发现Hsp 90抑制剂作为新的有效的抗癌药物。在这里，我们报告的识别一类新的Hsp 90抑制剂的生物物理FAXS-NMR为基础的筛选的片段库的装置。使用X-射线结构信息结合建模研究，使初始的三唑并喹唑啉击中一类化合物的片段演变与纳摩尔效力和药物样的性质，适合进一步的铅优化。(C)2014爱思唯尔有限公司版权所有。
In the last decade the heat shock protein 90 (Hsp90) has emerged as a major therapeutic target and many efforts have been dedicated to the discovery of Hsp90 inhibitors as new potent anticancer agents. Here we report the identification of a novel class of Hsp90 inhibitors by means of a biophysical FAXS-NMR based screening of a library of fragments. The use of X-ray structure information combined with modeling studies enabled the fragment evolution of the initial triazoloquinazoline hit to a class of compounds with nanomolar potency and drug-like properties suited for further lead optimization. (C) 2014 Elsevier Ltd. All rights reserved.