oncology projects, leveraging interactions with specific protein residues, active and
inactive conformations, and stable/unstable water molecules in the ATP cleft.
2 Discovery of an Exquisite Selective Aurora Inhibitor
as Neo-Cytotoxic Agent
The Aurora kinases exist as three isoforms (A, B, C), belong to the serine/threonine
protein kinase family, and regulate cell division. The Aurora kinases are expressed
and active predominantly during the G2/M phase of the cell cycle [31]. These
kinases are involved in the control of the centrosome and nuclear cycles and have
essential functions in mitotic processes such as chromosome condensation, spindle
dynamics, kinetochore-microtubule interactions, chromosome orientation, and
establishment of the metaphase plate. Each Aurora isoform has its own function
during mitosis in line with its specific distinct localization, namely, the centrosomes
and spindle poles for Aurora A and the centromeres and spindle mid-zone for Aurora
B. Aurora A and Aurora B kinases are expressed in all dividing cells, whereas
Aurora C kinase is mainly expressed in the testes and plays a role in spermatogenesis
[32–34].
D 274- F 275- G 276
C Glu181
N-lobe Lys162
GK Leu210
H 254- R 255- D 256
Cat Lys258
Tyr 212- Ala 213- Pro 214
Hinge
Phosphorylation
Thr287&288
Aurora A
active
site
Ile253
Ile253
Val252
Gly216
Leu263
Trp277
GRL
Lys141
C
Gln185
Ala273
Leu208
GRL
Phe144
Leu196
Ile209
Thr217
Fig. 3 KMM of Aurora A with privileged residues indicated
Achieving High Levels of Selectivity for Kinase Inhibitors
99