Aurora kinase inhibitors

Structure-Activity Relationships of Aurora Kinase Inhibitors... 

Tauchi T, Akahane D, Nunoda K et al. Activity of a novel aurora kinase inhibitor, VE-465, against T315i mutant form of BCR-ABL in vitro and in vivo studies (Abstract 1358). Blood 2006 108 396a. 

Error correction is thought to occur by stabilizing correct attachments while destabilizing incorrect attachments (41). Experiments in yeast showed that the inhibition of the Ipll/Aurora family of kinases prevents error correction by stabilizing incorrect attachments (38, 42), but how the active kinase corrected attachment errors was not known. This problem was particularly difficult to address because attachment errors are observed infrequently in the presence of active Aurora kinase (43). Experimental approaches that accumulated attachment errors through inhibition of Aurora kinase, for example by genetic mutation (42), did not permit subsequent kinase activation to examine error correction. Reversible small-molecule Aurora kinase inhibitors present a solution to this problem because they can be used to inhibit kinase function and subsequently removed to activate the kinase. 

Figure 4 Correction of improper chromosome attachments by activation of Aurora kinase (45). (a) Assay schematic, (i) Treatment with the Eg5 inhibitor monastrol arrests cells in mitosis with monopolar spindles, in which sister chromosomes often are both attached to the single spindle pole, (ii) Hesperadin, an Aurora kinase inhibitor, is added as monastrol is removed. As the spindle bipolarizes with Aurora kinase inhibited, attachment errors fail to correct so that some sister chromosomes are still attached to the same pole of the bipolar spindle, (iii) Removal of hesperadin activates Aurora kinase. Incorrect attachments are destabilized by disassembling the microtubule fibers, which pulls the chromosomes to the pole, whereas correct attachments are stable, (iv) Chromosomes move from the pole to the center of the spindle as correct attachments form, (b) Structures of the Eg5 inhibitor monastrol and two Aurora kinase inhibitors, hesperadin and AKI-1. (c) Spindles were fixed after bipolarization either in the absence (i) or presence (ii) of an Aurora kinase inhibitor. Arrows indicate sister chromosomes that are both attached to the same spindle pole. Projections of multiple image planes are shown, with optical sections of boxed regions (1 and 2) to highlight attachment errors. Scale bars 5 xm. (d) After the removal of hesperadin, GFP-tubulin (top) and chromosomes (bottom) were imaged live by three-dimensional confocal fluorescence microcopy and DIC, respectively. Arrow and arrowhead show two chromosomes that move to the spindle pole (marked by circle in DIC images) as the associated kinetochore-microtubule fibers shorten and that then move to the center of the spindle. Time (minutes seconds) after the removal of hesperadin. Scale bar 5 (cm.

Heron, N.M., Anderson, M., Blowers, D.R, et al. (2005) SAR and inhibitor complex structure determination of a novel class of potent and specific Aurora kinase inhibitors. Bioorg. Med. Chem. Lett. 16, 1320-3. 

An example of this is provided by the work of Girdler et al. on Aurora kinases.95 In this case, the candidate Aurora kinase inhibitor ZM-447439 (5.26) was incubated with HCT-116 cells, starting with a low concentration of the... 

Long-term Responses to Aurora Kinase Inhibitors In Vitro 446... 

The use of Aurora kinase inhibitors as anticancer drugs requires that they efiiciently kill their target... 

Gadea, B. B., Ruderman, J. V. (2005). Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts. Molecular Biology of the Cell, 16, 1305—1318. 

G. I. (2006). The Aurora kinase inhibitor VX-680 induces endor-eduplication and apoptosis preferentially in cells with compromised p53-dependent postmitotic checkpoint function. Cancer Research, 66, 7668—7677. 

Keen, N., 8c Taylor, S. (2004). Aurora-kinase inhibitors as anticancer agents. Nature Reviews. Cancer, 4, 927—936. 

Figure 1.10 Hesperadin, an Aurora kinase inhibitor, which interferes with mitosis.

Johan et al. [75] s)tnthesized a unique sequence for Aurora kinase inhibitors enclosing thiazole moiety (SNS-314,24). Also, key SAR as well as essential binding elements has been explained. 

Figure 5.16 Identification of Aurora kinase inhibitors applying a bis-thiol extender to the tethering approach.

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