title: Discovery of an Aurora kinase inhibitor through site-specific dynamic combinatorial chemistry.
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.
authors.affiliation: Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard, Suite 400, South San Francisco, CA 94080, USA.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Cancilla
authors.forename: Molly M
authors.initials: MM
authors.lastname: He
authors.forename: Nina
authors.initials: N
authors.lastname: Viswanathan
authors.forename: Robert L
authors.initials: RL
authors.lastname: Simmons
authors.forename: Meggin
authors.initials: M
authors.lastname: Taylor
authors.forename: Amy D
authors.initials: AD
authors.lastname: Fung
authors.forename: Kathy
authors.initials: K
authors.lastname: Cao
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Erlanson
mesh_terms: D064127:Aurora Kinases; D001665:Binding Sites / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D008024:Ligands; D013058:Mass Spectrometry / Q000379:methods; D008956:Models, Chemical; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011687:Purines / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D011687:Purines; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C030985:purine