Drugs That Inhibit Signaling Pathways for Tumor Cell Growth and Proliferation: Kinase Inhibitors

One of the fastest growing areas of research in cancer chemotherapy is the field of the “signal transduction inhibitors” or “secondary messenger inhibitors,” which has led to “molecularly targeted agents.” Chapter 10 deals with the most relevant signaling pathways related to kinases, and has a rather high complexity because of the large number of clinically validated kinases and kinase inhibitors. Many of these inhibitors are small molecules or monoclonal antibodies that have been approved for clinical use, or at least have entered clinical trials. All are classified and discussed according to their main target, usually accompanied by a brief description of the basis of their biological activity and, when possible, by a pictorial representation. The discovery and design of new entities, their structure (in the case of small molecules), and their anticancer applicability have also been considered of relevant value. Because of the large percentage of human tumors containing RAS mutants and their key role in maintaining the malignant phenotype, the several known ways to indirectly or directly modulate the Ras signaling pathway are discussed in detail, also showing the relevance among the multiple Ras effectors of the Raf kinase–MEK–MAPK (ERK) pathway, whose activity is increased in approximately one-third of all human cancers. The extracellular signal-regulated kinases (ERKs) catalyze the phosphorylation of hundreds of cytoplasmic and nuclear substrates. Some inhibitors of b-Raf that have been approved for different cancer types, inhibitors of MEKs that have entered clinical trials, and research efforts toward developing ERK inhibitors, have also been considered. Although the development of JNKs and p38 MAPK inhibitors in the treatment of cancer is in the infancy, the first molecules that have entered into clinical trials are discussed, as well as the inhibition of the corrupted signaling pathway known as transforming growth factor-β (TGF-β)–Smad signaling. The inhibition of kinases involved in glycolysis, as an effective strategy to kill cancer cells and overcome drug resistance associated with mitochondrial defects and hypoxic conditions, is also briefly discussed.