PROTAC-based protein degradation: a window of opportunity for melanoma therapy

The key small molecule-based modalities for inducing targeted protein degradation have seen explosive growth over the past decade. They include heterobifunctional degraders such as PROteolysis TArgeting Chimeras (PROTACs): molecules working as protein degraders by inducing proximity between a protein of interest, mostly a disease-causing protein, and an ubiquitin E3 ligase to trigger protein ubiquitination and degradation. The power of PROTACs has been broadly demonstrated, and their success has motivated interest and efforts in expanding the concept to several diseases including cancer, in the hope to tackle previously elusive or inadequately drugged targets and accelerate translation to clinical therapies. Some PROTACs have advanced to clinical development, confirming the efficacy and feasibility of this innovative therapeutic approach. Today, over 40 degraders, including PROTACs, are being developed in clinical trials, many for oncology indications. Although the literature is particularly abundant in reviews on PROTACs, there are currently no studies that collect data on the use of PROTACs in cutaneous melanoma, the most common and aggressive type of skin cancer. Therefore, in this comprehensive review, preclinical findings will be presented and discussed, helping to bring together studies and efforts in the rapidly evolving field of PROTACs, with regard to cutaneous melanoma. Thus, offering an opportunity for scientists and clinicians to deepen their knowledge about this field, and to shape the future of personalized cancer therapy.