Unraveling the Role of Linker Design in Proteolysis Targeting Chimeras

A current bottleneck in the development of proteolysis targeting chimeras (PROTACs) is the empirical nature of linker length structure–activity relationships (SARs). A multidisciplinary approach to alleviate the bottleneck is detailed here. First, we examine four published synthetic approaches that have been developed to increase synthetic throughput. We then discuss advances in structural biology and computational chemistry that have led to successful rational PROTAC design efforts and give promise to de novo linker design in silico. Lastly, we present a model generated from a curated list of linker SARs studies normalized to reflect how linear linker length affects the observed degradation potency (DC50).