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Strategies for cancer drug discovery have evolved in step with the explosion of knowledge about the molecular underpinnings of cancer. Many new drugs either recently approved or in late stages of evaluation were designed to block the fundamental mutations that cause specific cancers: aberrant growth factor receptors, dysregulated intracellular signaling pathways, defective DNA repair and apoptosis, and tumor angiogenesis. The primary tools for inhibiting these new targets are either monoclonal antibodies that attack cell surface receptors and antigens, or synthetic small molecules that enter cells and engage critical enzymes. These two classes of drugs have very different pharmacological properties.

Monoclonal antibodies kill tumor cells by blocking cell surface receptor function and by recruiting immune cells and complement to the antigen–antibody complex. They may be armed to carry toxins or radionuclides to the cells of interest, thereby enhancing their cytotoxic effects. They generally are specific for a single receptor, have a long plasma t1/2, and require only intermittent administration. Small molecules may attack the same targets and pathways as the monoclonals, but may also exert their effect by entering cells and inhibiting enzymatic functions (usually tyrosine kinase reactions). The small molecules often inhibit multiple enzymatic sites, have a broad spectrum of target kinases, and tend to be substrates of hepatic CYPs with a t1/2 of 12-24 hours, and thus require daily oral administration. The two classes of drug, when targeted against the same pathway, may have significantly different spectra of antitumor activity. Thus, monoclonal antibodies to the epidermal growth factor receptor (EGFR) are effective in the treatment of head and neck and colon cancers, while small molecules, such as erlotinib and gefitinib, attack the intracellular tyrosine kinase function of the same receptor and have a different spectrum of antitumor activity (non–small cell lung cancer).

Because of the central importance of the specific target in cancer chemotherapy, we will center this discussion around the target rather than the specific type of drug.


Protein kinases are critical components of signal transduction pathways that regulate cell growth and adaption to the extracellular environment. These signaling pathways influence gene transcription and/or DNA synthesis, as well as cytoplasmic events. The human genome contains ~550 protein kinases and 130 phosphoprotein phosphatases that regulate the phosphorylation states of key signaling molecules. Protein kinases can be classified into three different categories: kinases that specifically phosphorylate tyrosine residues, kinases that phosphorylate serine and threonine residues, and kinases with activity toward all three residues. Tyrosine kinases can be further subdivided into proteins that have an extracellular ligand-binding domain (receptor tyrosine kinases) and enzymes that are confined to the cytoplasm or nuclear cellular compartment (nonreceptor tyrosine kinases). Growth factors and other ligands bind to and activate the receptor tyrosine kinases under physiological conditions. In a growing number of human malignancies, mutations that constitutively activate protein tyrosine kinases are implicated in malignant transformation; ...

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