Anti-hormone Therapy

252 K.J. Moriarty et al.
panies. As a result of this work, the first Aurora kinase inhibitors, VX-680
(71), AZD1152 (92), and MLN8054 (97), have now progressed to clinical trials
and data from these studies are awaited.
3.2
Structural Biology of the Aurora Kinases
3.2.1
Aurora-A
AstraZeneca, Pharmacia, Vertex, Syrrx, and the European Molecular Biology
Laboratory (EMBL) have reported crystal structures of Aurora-A [149, 155–
160]. All the crystal structures of Aurora-A are of N-terminal truncated catalytic
domains. The structures published by Vertex and Syrrx are of unphosphorylated
Aurora-A co-crystallized with adenosine and ADP, respectively.
Three crystal structures reported from EMBL are of doubly phosphorylated
Aurora-A (Thr287, Thr288), one with bound ATP, one with ADP, and one consisting
of an ADP complex with the activating microtubule-associated protein
TPX2. AstraZeneca and Pharmacia (Nerviano Medical Sciences) have both reported
crystal structures with small molecule inhibitors bound to the active
sites of mutant forms of Aurora-A with point mutations at T287D and T288D.
The structure of Aurora-A has the typical bilobal kinase motif, consisting of
a β-sheet containing the N-terminal domain and a C-terminal domain comprised
mainly of α-helices. These domains are linked together by the typical
“hinge” region that plays an important role in forming the catalytic active site
(Fig. 8) [161, 162].
Fig. 8 Ribbon structure of Aurora-A