Rational Drug Design of Small Molecule Anticancer Agents: Preclinical Discovery

Abstract

In this chapter we review the development of small molecule inhibitors that act on targets involved in the causation and progression of human cancer. Considerable success has been achieved with drugs like imatinib and erlotinib that demonstrate the clinical utility of the molecular targeted approach. However, the success rate for cancer drugs in clinical development is only 1 in 20. We review the technologies that are being implemented to improve the success rate and increase the speed of preclinical oncology drug development. Topics covered include the selection and validation of drug targets, with emphasis on the genetics and biology of the disease, as well as on “druggability”; the generation of chemical “leads”, including various high‐throughput screening approaches; the use of structure‐based drug design, particularly using X‐ray crystallography; the value of chemical biology approaches; and the importance of biomarkers for patient selection and rational drug development. The integrated use of these technologies is illustrated using selected case histories. The chapter concludes with a look into the future and an assessment of the likely progress towards the development of bespoke cancer medicine. This chapter is followed by a companion chapter in which we review the clinical development of targeted molecular therapeutics.