Contemporary Developments in PROTACs for Cancer Management: An In-Depth Review

Proteolysis-Targeting Chimeras (PROTACs) represent a novel and promising cancer treatment strategy considered a direct alternative to conventional small-molecule inhibitors. PROTACs selectively degrade disease-causing proteins (including previously 'undruggable' targets such as transcription factors and scaffolding proteins) by harnessing the cellular ubiquitin proteasome system. In this review, we look at the most recent developments in PROTAC technology and their oncology applications. Versatility, while maintaining substrate selectivity and degradation efficiency, has also been enhanced by the expanded range of E3 ligases used in PROTAC design. Improvements in the stability, bioavailability, and systemic delivery of PROTACs are being achieved through innovations in pharmacokinetics and cell permeability, enabling their clinical translations. Initial clinical trials have confirmed the potential of these agents in human patients, and early preclinical studies have shown them to be highly efficacious in models of solid tumors and hematologic malignancies. Despite these encouraging developments, crucial challenges remain, including reducing off-target effects, addressing resistance mechanisms, and clarifying the significance of PROTAC-mediated degradation pathways. Future efforts must focus on refining the selectivity and tunability of degrader compounds, enhancing treatment efficacy via combination therapies, and optimizing PROTAC design through computational and structural biology. As the field continues to evolve, PROTACs remain a highly promising strategy for addressing unmet clinical needs in oncology. In this review, recent advancements in PROTAC technology are discussed, along with its contribution to cancer therapy and ways to circumvent existing challenges to its full therapeutic potential.