Targeted inhibition of kinases in cancer therapy

Abstract

With an understanding of the molecular changes that accompany cell transformation, cancer drug discovery has undergone a dramatic change in the past few years. Whereas most of the emphasis in the past has been placed on developing drugs that induce cell death based on mechanisms that do not discriminate between normal and tumor cells, recent strategies have emphasized targeting specific mechanisms that have gone awry in tumor cells. However, the identification of cancer-associated mutations in oncogenes and their amplification in tumors has suggested that inhibitors against such proteins might represent attractive substrates for targeted therapy. In the clinic, the success of imatinib (Gleevec®, STI571) and trastuzumab (Herceptin®), both firsts of their kind, spurred further development of new, second-generation drugs that target kinases in cancer. This review highlights a few important examples each of these types of therapies, along with some newer agents that are in various stages of development. Second-generation kinase inhibitors aimed at overriding emerging resistance to these therapies are also discussed.

Figure 1

Structures of imatinib, nilotinib, dasatinib, gefitinib and erlotinib.

Figure 2

Schematic representation of the BCR-ABL protein. The positions of 10 of the most common mutations in the kinase domain that confer imatinib resistance are shown. (Note: not drawn to scale).

Figure 3

Schematic representation of the EGFR. The positions of the most commonly identified mutations are shown. (Note: not drawn to scale).