Prospects and advances of PROTAC in the treatment of hematologic malignancies.

Abstract

Over the past years, target protein degradation (TPD) has emerged as a hot topic in treating hematologic malignancies out of its strong ability to eliminate pathological proteins precisely. And as a flagship, Proteolysis-Targeting Chimeras (PROTACs) hijack the ubiquitin- proteasome system to catalytically degrade protein of interest (POI). Compared to small-molecule inhibitors (SMIs) and Chimeric antigen receptor T-cell (CAR-T) therapies, PROTACs exhibit distinct advantages in mechanism of action, toxicity profile, specificity, diversity of targets, and ability to overcome drug resistance. In this review, we comprehensively summarize PROTAC drugs that have entered clinical trials, with particular focus on eight candidates being developed for hematologic malignancies. We also classified 56 protein targets whose PROTACs are in pre-clinical stage into seven groups based on their functions, including "epigenetic regulators", "kinases", "RNA regulators", "transcriptional regulators", "protein regulators", and so on. In summary, this review synthesizes the current landscape of PROTAC therapeutics in hematologic malignancies and provides perspectives on future development directions.