Linkers in proteolysis targeting chimeras (PROTACs)
The linker is an active determinant of ternary complex geometry, cooperativity, and ADME behavior in proteolysis targeting chimeras, not merely a passive connector.
Data-driven analysis of over 2700 proteolysis-targeting chimera linkers reveal a strong bias towards flexible, synthetically accessible chemotypes, leaving much of the available chemical space unexplored.
Clinical-stage proteolysis-targeting chimeras show marked convergence on alicyclic linkers, with polyethylene glycol-based architectures conspicuously absent, reflecting strong translational selection pressures.
The FDA approval of vepdegestrant (ARV-471) marks a significant milestone that positions linkerology as a central discipline in the development of next-generation proximity-based therapeutics.
Many apparent pharmacokinetic liabilities of degraders are, in essence, linker problems in disguise.
https://www.cell.com/trends/biochemical-sciences/fulltext/S0968-0004(26)00212-4
