| Motivated by the urgent need for new molecular targets and novel agents to treat pancreatic cancer, a target-based approach to drug discovery was implemented that led to the identification, validation and targeting of the Aurora family of kinases. The Aurora kinases (A, B and C) are mitotic serine/threonine kinases involved in various aspects of mitosis, including centrosome separation, bipolar spindle assembly, chromosome alignment and cytokinesis. In this dissertation, the potential use of the Aurora kinases as therapeutic targets to treat pancreatic cancer was investigated. It was found that both Aurora A and Aurora B are overexpressed in pancreatic adenocarcinomas, suggesting that some cancer cells are dependent upon their activity for continued proliferation and survival. To validate this hypothesis, antisense oligonucleotides were used in cell-based assays to evaluate the biological consequences of Aurora A and/or Aurora B inhibition. It was found that perturbations in Aurora kinase signaling result in cell cycle arrest and apoptosis. The biological fingerprints of Aurora A and Aurora B inhibition were compared and contrasted in an effort to identify the superior therapeutic target. It was concluded that an Aurora A-targeted therapy may have some beneficial consequences; however, a therapeutic approach discriminating between Aurora A and Aurora B is not straightforward. A fragment-based approach relying heavily on computer modeling was used to design and identify a nanomolar inhibitor of the Aurora kinases; however, it showed activity only at high micromolar concentrations in cell-based evaluations suggesting the compound possessed unfavorable characteristics that limited its biological activity. The preclinical development of analogues of the compound discovered by the work presented in this dissertation is ongoing. Finally, the pancreas-specific overexpression of Aurora A kinase was shown to be insufficient to induced pancreatic tumorigenesis in a mouse transgenic model. |
