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通过基于结构的设计发现的新型70 kDa热休克蛋白的腺苷衍生抑制剂。

Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design.

作者信息

Williamson Douglas S, Borgognoni Jenifer, Clay Alexandra, Daniels Zoe, Dokurno Pawel, Drysdale Martin J, Foloppe Nicolas, Francis Geraint L, Graham Christopher J, Howes Rob, Macias Alba T, Murray James B, Parsons Rachel, Shaw Terry, Surgenor Allan E, Terry Lindsey, Wang Yikang, Wood Mike, Massey Andrew J

机构信息

Vernalis (R&D) Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom.

出版信息

J Med Chem. 2009 Mar 26;52(6):1510-3. doi: 10.1021/jm801627a.

DOI:10.1021/jm801627a
PMID:19256508
Abstract

The design and synthesis of novel adenosine-derived inhibitors of HSP70, guided by modeling and X-ray crystallographic structures of these compounds in complex with HSC70/BAG-1, is described. Examples exhibited submicromolar affinity for HSP70, were highly selective over HSP90, and some displayed potency against HCT116 cells. Exposure of compound 12 to HCT116 cells caused significant reduction in cellular levels of Raf-1 and Her2 at concentrations similar to that which caused cell growth arrest.

摘要

本文描述了在HSC70/BAG-1复合物的建模和X射线晶体结构指导下，新型腺苷衍生的HSP70抑制剂的设计与合成。实例显示对HSP70具有亚微摩尔亲和力，对HSP90具有高度选择性，并且一些对HCT116细胞显示出效力。将化合物12暴露于HCT116细胞会导致Raf-1和Her2的细胞水平在与导致细胞生长停滞的浓度相似的浓度下显著降低。

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