De novo design and optimization of Aurora A kinase inhibitors
Drug discovery programs urgently seek new chemical entities that meet the needs of a demanding pharmaceutical industry. Consequently, de novo ligand design is currently re-emerging as a novelty-generating approach. Using ligand-based de novo design software, we computationally generated, chemically synthesized and biochemically tested a new arylsulfonamide against Aurora A kinase, a validated drug target in several types of cancer. The designed compound exhibited desired direct inhibitory activity against Aurora A kinase. By chemical optimization we obtained a lead structure exhibiting sustained activity in phenotypic assays. These results emphasize the potential of ligand-based de novo design to consistently deliver functional new chemotypes within short timeframes and limited effort. © 2013 The Royal Society of Chemistry.
Rodrigues, T; Roudnicky, F; Koch, CP; Kudoh, T; Reker, D; Detmar, M; Schneider, G
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