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Publication 41  

  1. Diversity-Oriented Synthesis of Pochonins and Biological Evaluation against a Panel of Kinases
    E. Moulin, S. Barluenga, F. Totzke, N. Winssinger
    Chem. Eur. J. 2006, 12, 8819-8834

Kinase inhibitors: Despite the lack of homology to purine analogues, pochonins have been shown to be ATPase inhibitors. A library of pochonins extending beyond the natural analogues was prepared by using solid-supported reagents. Screening the library against a panel of 24 kinases revealed a high number of inhibitors against therapeutically relevant kinases, such as Src, Aurora, and EGF-R, in contrast to pochonin D, which has no measurable kinase activity.

Pochonins A-F were recently characterized as six new members of the naturally occurring family of 14-membered resorcylic acid lactones. As there are a high number of ATPase and kinase inhibitors among natural resorcylic lactones, a library based on the pochonin scaffold, with five points of diversity, was prepared which includes diversity beyond that of the natural analogues. The library was synthesized by using solid-supported reagents amenable to automation. Testing the library for its inhibition against a panel of 24 kinases at 10 μm afforded a >14 % hit rate. These results demonstrate the potential of the resorcylides towards the inhibition of therapeutically relevant kinases.

 

DOI: 10.1002/chem.200600553 

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