E3 Ligases Meet Their Match: Fragment-Based Approaches to Discover New E3 Ligands and to Unravel E3 Biology

[Image: see text] Ubiquitination is a key post-translational modification of proteins, affecting the regulation of multiple cellular processes. Cells are equipped with over 600 ubiquitin orchestrators, called E3 ubiquitin ligases, responsible for directing the covalent attachment of ubiquitin to substrate proteins. Due to their regulatory role in cells, significant efforts have been made to discover ligands for E3 ligases. The recent emergence of the proteolysis targeting chimera (PROTAC) and molecular glue degrader (MGD) modalities has further increased interest in E3 ligases as drug targets. This perspective focuses on how fragment based lead discovery (FBLD) methods have been used to discover new ligands for this important target class. In some cases these efforts have led to clinical candidates; in others, they have provided tools for deepening our understanding of E3 ligase biology. Recently, FBLD-derived ligands have inspired the design of PROTACs that are able to artificially modulate protein levels in cells.