A class of 2,4-bisanilinopyrimidine Aurora A inhibitors with unusually high selectivity against Aurora B.
The two major Aurora kinases carry out critical functions at distinct mitotic stages. Selective inhibitors of these kinases, as well as pan-Aurora inhibitors, show antitumor efficacy and are now under clinical investigation. However, the ATP-binding sites of Aurora A and Aurora B are virtually identical, and the structural basis for selective inhibition has therefore not been clear. We report here a class of bisanilinopyrimidine Aurora A inhibitors with excellent selectivity for Aurora A over Aurora B, both in enzymatic assays and in cellular phenotypic assays. Crystal structures of two of the inhibitors in complex with Aurora A implicate a single amino acid difference in Aurora B as responsible for poor inhibitory activity against this enzyme. Mutation of this residue in Aurora B (E161T) or Aurora A (T217E) is sufficient to swap the inhibition profile, suggesting that this difference might be exploited more generally to achieve high selectivity for Aurora A.
Aliagas-Martin
Ignacio
I
Department of Small Molecule Drug Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
Burdick
Dan
D
Corson
Laura
L
Dotson
Jennafer
J
Drummond
Jason
J
Fields
Carter
C
Huang
Oscar W
OW
Hunsaker
Thomas
T
Kleinheinz
Tracy
T
Krueger
Elaine
E
Liang
Jun
J
Moffat
John
J
Phillips
Gail
G
Pulk
Rebecca
R
Rawson
Thomas E
TE
Ultsch
Mark
M
Walker
Leslie
L
Wiesmann
Christian
C
Zhang
Birong
B
Zhu
Bing-Yan
BY
Cochran
Andrea G
AG
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases