Preclinical and Clinical Advances of Targeted Protein Degradation as a Novel Cancer Therapeutic Strategy: An Oncologist Perspective

PROteolysis Targeting Chimeras (PROTACs) are a family of heterobifunctional small molecules that specifically target cellular proteins for degradation. Given that their mode of action is distinct from that of small-molecule inhibitors widely used in clinical practice, PROTACs have the potential to improve current cancer therapies. Multiple studies have suggested that PROTACs exhibit enhanced pharmacodynamics and reduced toxicity both in vitro and in vivo compared to clinically relevant small-molecule kinase inhibitors. In addition, PROTACs have been reported to be less prone to mutation-mediated drug resistance in specific disease settings. Since its development in 2001, the field of targeted protein degradation, in which PROTACs are used, has expanded rapidly. However, earlier studies focused on the advancement of the technology itself, while preclinical and clinical data on the disease-modifying effect of PROTACs have only recently been reported. As preclinical and clinical evidence accumulates, the efficacy of PROTACs as targeted therapeutics—distinct from that of small-molecule kinase inhibitors—suggests potential translational benefit in the clinical setting. In this short review, we aim to describe translational potentials of PROTACs. We offer our perspectives as practicing oncologists on the preclinical and clinical data on PROTACs as novel therapeutics for both solid and hematological malignancies.