PROTAC degraders for lymphoid malignancies - current status and future directions

Despite remarkable advances in targeted therapy, some patients with lymphoid malignancies develop resistance to all available treatment modalities. Proteolysis-targeting chimeras (PROTACs), harness the ubiquitin-proteasome system to eliminate both catalytic and scaffolding protein functions of disease-causing proteins, offering a strategy to overcome this resistance.

This review discusses the mechanisms of PROTAC activity, current preclinical and clinical data across lymphoid malignancies, and challenges for this emerging therapeutic class. PubMed, Google Scholar, and major hematology conference proceedings (ASH, ASCO, EHA) from 2017 to April 2026 were reviewed. Search terms included combinations of: PROTAC, targeted protein degradation, cereblon, von Hippel-Lindau, combined with individual disease terms and target names.

Among PROTACs, BTK degraders, tacabrutideg (BGB-16673) and bexobrutideg (NX-5948), have demonstrated overall response rates exceeding 75% in heavily pretreated relapsed/refractory CLL/SLL. The STAT3 degrader KT-333 and the IKZF1/3 degrader cemsidomide (the so-called molecular glue) have shown proof-of-concept clinical activity in T-cell and Hodgkin lymphomas. The durability of responses, long-term safety and predictive biomarkers have yet to be defined.The ongoing phase III trial of tacabrutideg will likely determine whether PROTACs become an established treatment option in lymphoid malignancies.