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Novel Adenosine-Derived Inhibitors of 70 kDa Heat Shock Protein, Discovered Through Structure-Based Design

2009; American Chemical Society; Volume: 52; Issue: 6 Linguagem: Inglês

10.1021/jm801627a

1520-4804

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

Insect and Pesticide Research

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.