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J Med Chem. 2008 Aug 28;51(16):4890-8. doi: 10.1021/jm800453a. Epub 2008 Aug 5.

Redesigning kinase inhibitors to enhance specificity.

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Department of Bioengineering, Rice University, Houston, Texas 77005, USA.


Kinases are important targets in molecular cancer therapy. However, the evolutionary relatedness and structural conservation of these proteins often lead to unforeseen cross reactivity, yielding unexpected side effects. Thus, the use of promiscuous drugs is likely to introduce dangerous clinical uncertainties. Here, we show how to rationally redesign two promiscuous kinase inhibitors, staurosporine (7) and EKB-569 (8), with the goal of turning them into more selective ligands. This problem is addressed by exploiting a structure-based selectivity filter for specificity: the pattern of packing defects in the target. These singularities, called dehydrons, are solvent-exposed intramolecular hydrogen bonds that may be protected by drugs upon association and are not conserved across protein families. Our redesigned compounds possess a significantly focused activity, as experimentally corroborated in high-throughput screening assays. Thus, our design strategy proves to be operative to reduce the inhibitory impact of promiscuous kinase ligands, enhancing their safety as therapeutic agents.

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