Allosteric PROTACs: Expanding the Horizon of Targeted Protein Degradation
Aileen B. Frost, Suzanne O’Connor, Alessio Ciulli
Abstract
Proteolysis-targeting chimeras (PROTACs) have transformed the concept of chemical intervention in biological systems by co-opting the ubiquitin-proteasome system to selectively degrade proteins. A key promise of this modality is that proximity alone─not inhibition─is required, allowing binding anywhere on the protein surface to trigger degradation. Yet despite this conceptual freedom, most PROTACs to date have been built from orthosteric inhibitors. The use of allosteric or functionally silent ligands remains a largely untapped opportunity. In this Perspective, we spotlight pioneering efforts in allosteric PROTAC design and explore how such strategies could unlock improved outcomes for target selectivity, efficacy, and resistance management while also modulating physicochemical properties to enhance in vivo performance. We further discuss the practical and conceptual challenges and the advances needed to make allosteric targeting a mainstream strategy in the design of protein degraders and other proximity-inducing molecules.