Abstract
Bruton's tyrosine kinase (BTK) plays an important role in B-cell development and has become a well-established target in B-cell malignancies. Over the past two decades, BTK inhibitors (BTKis) have transformed the treatment landscape for chronic lymphocytic leukemia (CLL) and other B-cell lymphoid malignancies. Despite their efficacy, acquired resistance to BTKis remains a significant challenge, highlighting the need for alternative therapeutic strategies. Targeted protein degradation has emerged as a promising approach to eliminate BTK and thereby inhibit both its kinase and non-kinase (i.e. scaffold) functions. Bexobrutideg (NX-5948) is a novel BTK degrader that was designed to overcome limitations associated with BTKis while maintaining favorable selectivity. In this review, we summarize the rationale for BTK degradation, discuss the preclinical and clinical evidence supporting bexobrutideg, and highlight remaining challenges and future directions for this emerging class of therapeutics.