Discovery of an Aurora kinase inhibitor through site-specific dynamic combinatorial chemistry

We demonstrate a fragment-based lead discovery method that combines site-directed ligand discovery with dynamic combinatorial chemistry. Our technique targets dynamic combinatorial screening to a specified region of a protein by using reversible disulfide chemistry. We have used this technology to rapidly identify inhibitors of the drug target Aurora A that span the purine-binding site and the adaptive pocket of the kinase. The binding mode of a noncovalent inhibitor has been further characterized through crystallography.

Graphical abstractWe demonstrate a fragment-based lead discovery method that combines site-directed ligand discovery with dynamic combinatorial chemistry to identify inhibitors of Aurora kinase A.Figure optionsDownload full-size imageDownload as PowerPoint slide