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Molecular Diversity

, Volume 16, Issue 1, pp 27–51 | Cite as

The generation of purinome-targeted libraries as a means to diversify ATP-mimetic chemical classes for lead finding

  • Eduard R. Felder
  • Alessandra Badari
  • Teresa Disingrini
  • Sergio Mantegani
  • Christian Orrenius
  • Nilla Avanzi
  • Antonella Isacchi
  • Barbara Salom
Full-Length Paper

Abstract

The generation of novel chemotypes in support of our oncology research projects expanded in recent years from a canonical design of kinase-targeted compound libraries to a broader interpretation of purinome-targeted libraries (PTL) addressing the specificity of cancer relevant targets such as kinases and ATPases. Successful screening of structurally diverse ATP-binding targets requires compound libraries covering multiple design elements, which may include phosphate surrogate moieties in ATPase inhibitors or far reaching lipophilic residues stabilizing inactive kinase conformations. Here, we exemplify the design and preparation of drug-like combinatorial libraries and report significantly enhanced screening performance on purinomic targets. We compared overall hit rates of PTL with a simultaneously tested unbiased collection of 200,000 compounds and found consistent superiority of the targeted libraries in all cases. We also analyzed the performance of the largest targeted libraries in comparison with each other and often found striking differences in how a specific target responds to various chemotypes and to whole collections.

Keywords

Combinatorial chemistry Compound collection Drug design Kinase inhibitors Chemical space Fragment based Solid phase synthesis ATPase inhibitors Kinase selectivity 

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Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Eduard R. Felder
    • 1
  • Alessandra Badari
    • 1
  • Teresa Disingrini
    • 1
  • Sergio Mantegani
    • 1
  • Christian Orrenius
    • 1
  • Nilla Avanzi
    • 1
  • Antonella Isacchi
    • 1
  • Barbara Salom
    • 1
  1. 1.Oncology ResearchNerviano Medical SciencesNervianoItaly

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