What It Takes to Improve a First-Generation Inhibitor to a Second- or Third-Generation Small Molecule

Since the first generation of small molecules was included in the armamentarium of treatment of solid tumors (imatinib, erlotinib, etc.), there has been an expansion of anticancer small molecules, mostly kinase inhibitors, in development. Some of these drugs may not be a real breakthrough but may be similar in pharmacologic properties and marginal benefit over previously existing agents for the same indication (i.e., me-too drugs). Other drugs, however, have been specifically designed to solve an unmet medical need. Overcoming the problems of the blood-brain barrier and brain metastasis, emerging resistance mutations (such as gatekeeper mutations), or increasing selectivity/potency can be addressed with modern drug design. In this article, we discuss the advancements in the field of drug discovery, drug development, and clinical development that have enabled solving some of these issues. The evolution of the different generations of EGFR and anaplastic lymphoma kinase inhibitors exemplifies recent advancements in pharmacology that are driving the field of anticancer small molecules as a whole.