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

Authors :: Cancilla MT
He MM
Viswanathan N
Simmons RL
Taylor M
Fung AD
Cao K
Erlanson DA
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2008 Jul 15; Vol. 18 (14), pp. 3978-81. Date of Electronic Publication: 2008 Jun 10.
Publication Year :: 2008
Abstract: 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.

Subjects :: Aurora Kinases
Binding Sites drug effects
Crystallography, X-Ray
Drug Design
Ligands
Mass Spectrometry methods
Models, Chemical
Molecular Structure
Purines chemistry
Structure-Activity Relationship
Chemistry, Pharmaceutical methods
Combinatorial Chemistry Techniques methods
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Protein Serine-Threonine Kinases antagonists & inhibitors

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