Despite the investment of substantial intellectual and ónancial resources in cancer research over the past 20 years, malignancies remain the second leading cause of death in the developed world. While improved surgical and radiotherapy techniques permit the cure of most patients who present localized tumors, only 10^ 12% of the patients with disseminated cancer are cured by existing chemotherapies [1]. Clearly, more effective treatments are needed. One approach to the identiócation of more effective therapeutics is to focus drug discovery efforts on the fundamental molecular mechanisms responsible for mammalian cell transformation. This approach is particularly attractive in the light of the dramatic expansion of our understanding of the biochemical, cell biological and genetic basis of cancer that has accrued in recent years. We now know that three types of genetic alterations or mutations underlie the pathogenesis of virtually all cancers. These mutations arise in oncogenes, tumor suppressor genes and genes that govern the faithful replication of DNA, eg DNA repair enzymes and cellular checkpoint genes. Unfortunately, most of the cancer causing mutations that arise in tumor suppressor genes and DNA repair enzymes result inloss of function'changes for the encoded proteins. Proteins suffering

loss of function'mutations make poor targets for the creation of drug therapies since small organic molecules are rarely capable of restoring the biologically active conformation to mutated proteins that are distorted or denatured. By contrast, mutations arising in oncogenes generally result ingain of function'changes for their encoded proteins. Oncogenes harboringgain of function'mutations are far more attractive targets for pharmaceutical intervention, because small organic molecules that block the enhanced activities of enzymes or ligands for specióc receptors are much more readily identióed using traditional drug screening strategies [2].