Discovery and Development of Aurora Kinase Inhibitors as Anticancer Agents

摘要

The process of cell division or mitosis is highly complex and tightly regulated. During this phase of the cell cycle two identical copies of DNA are completely separated by the microtubule spindle apparatus and packaged into two daughter cells (see Figure 1 for a description of mitosis). Inappropriate completion of mitosis leads to genetic instability and, frequently, cells that contain nondiploid DNA content (less than or greater than 2 copies of DNA). These phenotypes are hallmarks of nearly allhuman cancers.1 Targeting components of the mitotic machinery in order to block tumor progression has been an area of intense research. This effort has resulted in several marketed anticancer agents, which provide a proof of concept for the approach. Examples include the taxanes and the vinca alkaloids for which the principal target is the microtubule component of the mitotic spindle. More recently, alternative components of the mitotic machinery have been targeted in an attempt to develop novel anticancer agents. These include critical signaling kinases such as the Aurora, Plk, and the Cdk kinases and important motor proteins such as KSP1.