Many of the critical elements identified in signal transduction cascades that affect tumor growth and survival are kinases and, among the members of this large family of enzymes, a set of receptor tyrosine kinases (RTKs) has emerged as suitable targets for oncology drug discovery.

The complexity and number of RTKs being targeted in oncology drug discovery has greatly increased in the past few years, and it is impossible to capture all of the available information herein. Among the different approaches used to target these enzymes (e.g., monoclonal antibodies and kinase inhibitors), this chapter focuses on contributions in the inhibition of receptor tyrosine kinase activity by ATP-site directed competitive and irreversible compounds. The intent is to provide a comprehensive, rather than an exhaustive overview of the pertinent literature in this fascinating and challenging area of research. To start, we briefly describe key results and achievements for three RTKs (EGFR, c-Kit and FLT3) in which drug discovery and development activities have advanced with some success. After this, we have selected representative examples of a new wave of therapeutic targets (IGF-IR, c-MET, and RET) to illustrate new opportunities and challenges in the identification of drugs for tailored cancer treatment.

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