al for multiple levels of control with regard to the Mdmx response. 3. Kinase Inhibitors of the Mdm2 Mdmx p53 Axis The search for therapeutic kinase inhibitors has accelerated in the past decade with the majority PS-341 Proteasome inhibitor of research and development efforts aimed at the treatment of cancer. The reasons for the current interest in kinases as therapeutic targets are varied. There are greater than 500 kinases encoded by the human genome. Since signal transduction pathways predominantly involve phosphotransfer, many kinases are involved in processes that lead to tumor formation. Cell cycle and growth pathways are hyperactive in cancer and the normal control mechanisms that prevent kinase activation are often lost. Cells can also lose their responsiveness to growth factors due to aberrant kinase activity in mitogenic signaling cascades.
Thus, selective pharmacological compounds aimed at kinase activity have been Waning et al. Page 4 Pharmaceuticals. Author manuscript, available in PMC 2010 July 21. NIH PA Author Manuscript NIH PA Author Vincristine Manuscript NIH PA Author Manuscript successfully developed and approved for use in humans. Kinase inhibitors are usually well tolerated in normal cells allowing for selective treatment of tumor cells as the tumor cells often become addicted to signaling pathways provided by kinases. The multiple kinase signaling cascades that affect p53 are cumulatively important for full engagement of the tumor suppressive activities of p53. These include both the direct phosphorylation of p53 as well as modifications to p53,s negative regulators, Mdm2 and Mdmx.
The focus of this review is to identify the kinase modification events that target the Mdm2 Mdmx p53 axis in response to DNA damage. Table 3 lists important kinase inhibitors that target signaling events of Mdm2, Mdmx and p53. 3.1. Classes of kinase inhibitors Protein kinases are able to catalyze the transfer of the terminal phosphate of ATP to a target substrate. Protein kinases either target serine and threonine residues or tyrosine residues around some amino acid sequence specificity or structural specificity motif. ATP binding is typically in a deep pocket of the kinase active site. The majority of kinase inhibitors target the ATP binding site for competitive binding. Four different classes of kinase inhibitors have been identified.
Type I kinase inhibitors represent the largest class of kinase inhibitors and are competitive inhibitors of the kinase active conformation. Type II kinase inhibitors recognize the inactive conformation of the kinase typically through a hydrophobic patch near the ATP binding site that is only exposed in the inactive conformation. In addition to compounds that target the ATP binding site, a third type, the allosteric kinase inhibitors have been developed that modulate kinase activity. These compounds exhibit the highest degree of selectivity since their binding sites are independent of the well conserved kinase active site. This class of compounds also includes inhibitors that bind accessory molecules that are required for kinase activity. The fourth type of inhibitor is covalent inhibitors that form irreversible crosslinks to the kinase active site rendering it inactive.
In addition to the current compounds in development or trials, a large group of analogues that have modifications to the basic chemistry of the original lead compound are being designed to provide enhanced selectivity or lower toxicity. 3.2. Kinase inhibitors that target the Mdm2 Mdmx p53 axis Over the past decade pharmaceutical and academic researchers have begun to understand and target kinase signaling pathways that are involved in cancer development and metastasis. Much work has led to the appreciation that targeting kinases in cancer will likely require some rational