Epidermal Growth Factor Receptor as a Model Drug Target for Scrutinizing the Status Quo in Drug Discovery and Chemical Biology

Abstract

Drug discovery scientists and chemical biologists continually seek to improve strategies for compound development. Here, we present insights derived from multiple studies of the epidermal growth factor receptor (EGFR), illustrating how this well-established target can inform practical aspects of drug discovery. Case studies spanning fragment-based drug design, bivalent inhibitor discovery, and the optimization of irreversible covalent inhibitors demonstrate how focused investigation of a single system can serve as a framework for methodological innovation and generation of broadly applicable knowledge. We propose that these collective efforts exemplify an emerging paradigm in medicinal chemistry, wherein “model drug targets” are deliberately leveraged to yield generalizable design principles and uncover new strategies for ligand discovery and chemical probe development.