Targeted delivery of proteolysis-targeting chimeras (PROTAC) and molecular glue degraders (MGD).

چکیده اصلی

Targeted protein degraders (TPDs), including proteolysis-targeting chimeras (PROTAC) and molecular glue degraders (MGD), are among the most promising small-molecule-based drug treatments in oncology. The May 2026 U.S. Food and Drug Administration (FDA) approval of vepdegestrant provides a regulatory milestone for heterobifunctional protein degradation and for PROTAC therapeutics. First-generation TPDs were developed for oral delivery; however, the intrinsic physicochemical properties of TPDs impose constraints on their oral bioavailability, systemic exposure, target-site accumulation, and therapeutic efficacy. As the field transitions toward a second wave of TPD development, nanoparticle-based targeted protein degraders (nano-TPD) are gaining momentum for broadening the therapeutic landscape of protein degradation. In this context, drug delivery systems offer opportunities to overcome key translational barriers by improving pharmacokinetics, tissue distribution, target site localization, cellular uptake, and therapeutic index. Here, we provide an overview of TPD discovery, from early laboratory to (pre-) clinical progress, discuss translational challenges, and suggest advanced drug delivery solutions to help realize the full potential of TPD therapies.

متن کامل اصلی