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

J Cell Mol Med. 2025 Feb;29(3):e70170. doi: 10.1111/jcmm.70170.

Abstract

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.

Keywords: BTK inhibitors; Waldenstrom macroglobulinemia; chronic lymphocytic leukemia; follicular lymphoma; mantle cell lymphoma; marginal zone lymphoma; zanubrutinib.

Publication types

  • Review

MeSH terms

  • Agammaglobulinaemia Tyrosine Kinase* / antagonists & inhibitors
  • Agammaglobulinaemia Tyrosine Kinase* / metabolism
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Hematologic Neoplasms* / drug therapy
  • Humans
  • Piperidines* / pharmacology
  • Piperidines* / therapeutic use
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Pyrazoles* / chemistry
  • Pyrazoles* / pharmacology
  • Pyrazoles* / therapeutic use
  • Pyrimidines* / chemistry
  • Pyrimidines* / pharmacology
  • Pyrimidines* / therapeutic use
  • Tyrosine Kinase Inhibitors

Substances

  • zanubrutinib
  • Agammaglobulinaemia Tyrosine Kinase
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Piperidines
  • BTK protein, human
  • Antineoplastic Agents
  • Tyrosine Kinase Inhibitors