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Issue 7, 2012
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De novo design, synthesis and pharmacological evaluation of new azaindole derivatives as dual inhibitors of Abl and Src kinases

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Abstract

A new fragment based drug design approach implemented in our MedChem-Decision platform led to the discovery of a new series of 2,5 disubstituted 7-azaindole derivatives as potent dual Abl and Src kinase inhibitors. Extensive structure–activity relationships and structure-based drug design studies guided the exploration of the specificity pocket within the active conformation of the ATP site of the two kinases. This led to (1) the identification of a new binding mode of the 7-azaindole core to the two kinases and (2) the synthesis and pharmacological evaluation of compounds that exhibit low nanomolar inhibition on both Abl and Src kinases as well as moderate activity on the Abl 315I mutant.

Graphical abstract: De novo design, synthesis and pharmacological evaluation of new azaindole derivatives as dual inhibitors of Abl and Src kinases

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Article information


Submitted
28 Jan 2012
Accepted
06 May 2012
First published
19 Jun 2012

Med. Chem. Commun., 2012,3, 788-800
Article type
Concise Article

De novo design, synthesis and pharmacological evaluation of new azaindole derivatives as dual inhibitors of Abl and Src kinases

G. Chevé, C. Bories, B. Fauvel, F. Picot, A. Tible, B. Daydé-Cazals, O. Loget and A. Yasri, Med. Chem. Commun., 2012, 3, 788
DOI: 10.1039/C2MD20104F

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