Expanding the Scope of PROTACs: Opportunities and Challenges in Topical Delivery
Laura Gioiello, Rita Maria Concetta Di Martino, Tracey Pirali
Abstract
High Resolution Image Download MS PowerPoint Slide Proteolysis-targeting chimeras (PROTACs) have emerged as a novel therapeutic modality primarily through systemic administration. Recently, their topical use has drawn increasing attention, offering a promising strategy to achieve localized protein degradation while minimizing systemic toxicity. This miniperspective highlights key advances in the development of topical PROTACs, exemplified by AH-001 and GT20029, androgen receptor degraders, both in clinical trials for androgenetic alopecia, with GT20029 also evaluated for acne. We discuss emerging degraders that target clinically relevant proteins, including JAK kinases and BET family members, with applications extending beyond dermatology to pulmonary and ocular diseases and even cosmetic use. Innovative strategies, such as liposomes and microneedle systems, are also enabling effective local delivery. Despite this progress, topical PROTACs face some challenges, such as optimizing the stability, tissue penetration, and selective target engagement under physiological conditions. We conclude by outlining strategic directions that could accelerate the clinical translation of this emerging therapeutic modality.