Structural basis for the inhibition of Aurora A kinase by a novel class of high affinity disubstituted pyrimidine inhibitors.
The 2.25 A crystal structure of a complex of Aurora A kinase (AIKA) with cyclopropanecarboxylic acid-(3-(4-(3-trifluoromethyl-phenylamino)-pyrimidin-2-ylamino)-phenyl)-amide 1 is described here. The inhibitor binding mode is novel, with the cyclopropanecarboxylic acid moiety directed towards the solvent exposed region of the ATP-binding pocket, and several induced structural changes in the active-site compared with other published AIK structures. This structure provides context for the available SAR data on this compound class, and could be exploited for the design of analogs with increased affinity and selectivity for AIK.
Tari
Leslie W
LW
ActiveSight, 4045 Sorrento Valley Blvd., San Diego, CA 92121, USA.
Hoffman
Isaac D
ID
Bensen
Daniel C
DC
Hunter
Michael J
MJ
Nix
Jay
J
Nelson
Kirk J
KJ
McRee
Duncan E
DE
Swanson
Ronald V
RV
D000818:Animals; D064127:Aurora Kinases; D002460:Cell Line; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D066246:ErbB Receptors / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D011743:Pyrimidines; D066246:ErbB Receptors; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases