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

Mark T Cancilla; Molly M He; Nina Viswanathan; Robert L Simmons; Meggin Taylor; Amy D Fung; Kathy Cao; Daniel A Erlanson

doi:10.1016/j.bmcl.2008.06.011

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

Bioorg Med Chem Lett. 2008 Jul 15;18(14):3978-81. doi: 10.1016/j.bmcl.2008.06.011. Epub 2008 Jun 10.

Authors

Mark T Cancilla¹, Molly M He, Nina Viswanathan, Robert L Simmons, Meggin Taylor, Amy D Fung, Kathy Cao, Daniel A Erlanson

Affiliation

¹ Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard, Suite 400, South San Francisco, CA 94080, USA.

PMID: 18579375
DOI: 10.1016/j.bmcl.2008.06.011

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

Enzyme Inhibitors
Ligands
Purines
Aurora Kinases
Protein Serine-Threonine Kinases
purine