Rational design of the linkers in targeting chimeras

Abstract

Targeting chimeras (TACs), such as PROTACs, LYTACs, AUTACs, and ATTECs, have emerged as promising strategies for selectively degrading proteins, including undruggable targets. These approaches leverage bifunctional molecules or molecular glues to selectively degrade specific proteins, offering new therapeutic potential for the diseases that traditional small molecules cannot effectively address. The linker of the TACs serving as a bridge, connecting the target protein ligand and effector protein ligand, plays a critical role in determining the molecule's spatial conformation and overall activity. Recent advances in linker design strategies, such as photo-switchable, cleavable, and flexible linkers, have enhanced the efficacy, selectivity, and spatiotemporal control of TACs. Despite these advances, challenges remain in optimizing linker properties to balance stability, bioavailability, and pharmacokinetics. In this review, we discuss recent advancements in TACs development and summarize the strategies of linkers' design, including traditional/non-traditional, and functionalized linkers of various TACs. Finally, we highlight current challenges in linker design and explore future opportunities and strategies, hoping to provide inspiration for the development of TACs in drug discovery.