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Antiproliferation Inhibitors Targeting Aurora Kinases

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Checkpoint Responses in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development• ((CDD&D))

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Abstract

The family of serine-threonine (S/T) protein kinases Aurora A, B, and C regulate distinct functions and phases of mitosis within the cell cycle. Aurora A regulates centrosome maturation and spindle assembly while Aurora B (and C) a chromosome passenger protein (CPP) regulates chromosome orientation on the spindle and cytokinesis. All 3 Auroras are overexpressed in a multitude of human cancers with an associated polyploid phenotype containing multiple centrosomes. Aurora A and B when aberrantly overexpressed and dysregulated in an appropriate genetic background function as oncogenes by overriding cell-cycle checkpoints leading to errors in mitosis (aneuploidy) with subsequent chromosomal instability, a hallmark of human cancer. Over the past 5 years the biology of Aurora kinases in mitotic regulation has been further elucidated by RNA interference (RNAi), dominant-negative kinase mutants and several small molecular ATP-site competitive inhibitors. The availability of several crystal structures with bound ADP, several drugs and peptide fragments from interacting proteins have provided a detailed insight of the active site, biological functions, rationale for the mode of binding of a broad range of small molecular inhibitors and clues to the likelihood of developing resistance through point mutations. Homology models and crystal structures have also aided in fragment-based rational drug discovery of Aurora inhibitors including compounds specific for Aurora A and B respectively. Moreover, several Aurora kinase inhibitors have shown promising antitumor activity in rodent models of cancer. However, overexpression of Aurora A results in paclitaxel resistance owing to overriding of a spindle checkpoint and combination therapy studies are warranted to evaluate mechanisms of resistance. Despite these concerns, excitingly, over the past 2 years Aurora inhibitors have entered the phase I arena and are being evaluated in solid and hematological malignancies.

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Authors
  1. Kishore Shakalya
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  2. Daruka Mahadevan
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Editors and Affiliations

  1. Department of Environmental Medicine, New York University School of Medicine, Tuxedo, NY

    Wei Dai PhD

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© 2008 Humana Press, a part of Springer Science+Business Media, LLC

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Shakalya, K., Mahadevan, D. (2008). Antiproliferation Inhibitors Targeting Aurora Kinases. In: Dai, W. (eds) Checkpoint Responses in Cancer Therapy. Cancer Drug Discovery and Development•. Humana Press. https://doi.org/10.1007/978-1-59745-274-8_11

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