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).