Covalent Bruton tyrosine kinase inhibitors across generations: A focus on zanubrutinib

Bruton tyrosine kinase (BTK), the primary target of BTK inhibitors, is a key enzyme in the proliferation and survival pathway of neoplastic B-cells. BTK inhibitors are approved in many hematologic malignancies: chronic lymphocytic leukaemia, mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinaemia and follicular lymphoma. Second-generation BTK inhibitors display high target selectivity thus resulting in a reduction in off-target and off-tissue effects, better therapeutic index and improved tolerability. This paper summarizes the mechanisms of action of first and second generation BTK inhibitors and elucidates results in any disease setting, with a precise focus on zanubrutinib.