Chapter 12: The Discovery of Lapatinib

Protein kinases are now considered highly druggable due to the fact that there are kinase inhibitors on the market as effective drugs (e.g. Gleevec, Tarceva, and Nexavar). The class of drugs remains plagued by questions about how the inhibition profile affects the efficacy, and whether truly selective kinase inhibitors actually exist. Lapatinib remains one of the most selective kinase inhibitors in use for cancer therapy. This chapter will focus on our strategies to discover this novel, dual EGFR and ERBB-2 tyrosine kinase inhibitor using a carefully designed biological evaluation cascade coupled with a multidimensional data analysis. The primary topics discussed will cover the optimization of potency for two kinase targets, yet selective among over 500 kinases within the highly homologous ATP binding site, cellular selectivity and efficacy, and subsequent studies to understand the mechanism of action.