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.
Cancilla
Mark T
MT
Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard, Suite 400, South San Francisco, CA 94080, USA.
He
Molly M
MM
Viswanathan
Nina
N
Simmons
Robert L
RL
Taylor
Meggin
M
Fung
Amy D
AD
Cao
Kathy
K
Erlanson
Daniel A
DA
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
D004791:Enzyme Inhibitors; D008024:Ligands; D011687:Purines; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C030985:purine