ABSTRACT
This chapter introduces the molecularly targeted agents which were pioneered in the 1980s based on the concept of targeting biochemical pathways or proteins that are uniquely deregulated or mutated, respectively, in tumor cells. Theoretically, such agents should produce significantly less toxicity than the older families of anticancer drugs (i.e., the antimetabolites, tubulin inhibitors, and DNA-interactive agents), as the mutated proteins or deregulated pathways should not be present in healthy cells. A second important design concept was that molecularly targeted agents should be orally available so that patients could self-medicate, in contrast to the older families of cytotoxic agents that are mostly administered intravenously and require hospitalization. This concept was validated with the discovery of imatinib (GleevecTM) for the treatment of chronic myeloid leukemia (CML) in the 1990s. The main subfamilies of molecularly targeted agents are presented which includes the protein kinase, Hedgehog pathway, cell cycle, proteasome, phosphatidylinositol 3-kinase, apoptosis, HDM2-p53, retinoid, metastatic pathway, and heat shock protein inhibitors. Approved agents within each subfamily are described in detail along with information relating to their discovery, chemical structure, mechanism of action, pharmacology, clinical activity, and mechanism-based toxicity. A discussion of structure-activity relationships (SARs) is included within subfamilies where relevant. Prominent clinical-stage experimental agents within each subfamily are also described.
