Next-generation Bruton tyrosine kinase inhibitors and degraders in the treatment of B-cell malignancies: advances and challenges.

Bruton tyrosine kinase (BTK), a key component of B-cell receptor signaling, is crucial for the development of B-cell malignancies. Covalent BTK inhibitors (cBTKis), such as ibrutinib, have demonstrated remarkable efficacy, but their curative potential is limited by acquired resistance. Next-generation BTK inhibitors, including non-covalent BTK inhibitors and BTK Proteolysis-targeting chimeras, offer new options for patients who have developed resistance to cBTKis. Some of these inhibitors have shown favorable efficacy and safety profiles, leading to Food and Drug Administration approval. This review summarizes the current landscape of BTK inhibitors, focusing on the evolution from cBTKis to next-generation inhibitors in terms of clinical efficacy and challenges, such as resistance mechanisms and off-target effects. We conclude with an outlook on future research and clinical applications.