Discovery of Bexobrutideg (NX-5948), an Oral Targeted Degrader of Bruton's Tyrosine Kinase (BTK) for the Treatment of B-cell Malignancies

Bruton’s tyrosine kinase inhibitors (BTKi) are widely used for the treatment of B-cell malignancies. However, the emergence of BTKi resistance mutations is an increasing therapeutic challenge. B-cell receptor (BCR) signaling, maintained by BTK’s non-enzymatic scaffolding function, and further complicated by the development of inhibitor-driven resistance mutations in BTK, underscores the need for therapies that work through an alternative mechanism of action. Bexobrutideg (NX-5948) is an orally administered, heterobifunctional small molecule degrader that acts to selectively eliminate both wild-type and mutant BTK from cells via cereblon-mediated ubiquitination and proteasomal degradation. This presentation summarizes the discovery, preclinical characterization, and Phase 1a/b safety and efficacy findings for bexobrutideg.