Zanubrutinib is a covalent Bruton’s tyrosine kinase (BTK) inhibitor designed to deliver highly selective and sustained inhibition of BTK.1 Zanubrutinib was engineered to minimize off-target kinase inhibition while maintaining near-complete BTK target occupancy, with the goal of improved tolerability and durable clinical efficacy across B-cell malignancies.1,2
Zanubrutinib was rationally designed to improve upon the profile of ibrutinib, the first BTK inhibitor, by achieving:
In the ALPINE Phase 3 trial, zanubrutinib demonstrated superior progression-free survival and lower rates of atrial fibrillation compared with ibrutinib in patients with relapsed/refractory CLL/SLL.3
BTK, Bruton’s tyrosine kinase; BTKi, BTK inhibitor; EGFR, epidermal growth factor receptor; IC50, half-maximal inhibitory concentration; ITK, interleukin-2_inducible T-cell kinase; JAK3, Janus kinase 3; MCL, mantle cell lymphoma; TEC, tyrosine kinase expressed in hepatocellular carcinoma.
BTK is a central signaling kinase downstream of the BCR, regulating B-cell survival, proliferation, migration, and interaction with the tumor microenvironment via PLCɣ2, NF-ƘB, and MAPK pathways.1 Constitutive BCR signaling is a key oncogenic driver in CLL, MCL, WM, and other B-cell malignancies.1
BTK has a high turnover rate; with a de novo synthesis rate that varies from 3.6% to 31.4% per day and an estimated half-life of about 12 hours.2
Zanubrutinib forms an irreversible covalent bond with the Cys481 residue of BTK, leading to sustained inactivation of the kinase.3,4
Due to its high potency and favorable pharmacokinetics, zanubrutinib maintains complete BTK occupancy (100%) throughout the dosing interval and >95% BTK occupancy at trough concentrations, resulting in durable suppression of BCR signaling.2
Zanubrutinib is highly selective for BTK and achieves continuous BTK inhibition without reliance on active metabolites, which may have significant activity for other kinases and contribute to off-target toxicity.2-4 This mechanistic profile underpins zanubrutinib’s role as a foundational BTK inhibitor for both monotherapy and combination strategies.
BCR, B-cell receptor; BTK, Bruton’s tyrosine kinase; BTKi, BTK inhibitor; CLL, chronic lymphocytic leukemia; Cys481, cysteine at position 481; MAPK, mitogen-activated protein kinase; MCL, mantle cell lymphoma; NF-ƘB, nuclear factor kappa-light-chain-enhancer of activated B cells; PLCɣ2, phospholipase C gamma 2; WM, Waldenstrom’s macroglobulinemia.
BRUKINSA (zanubrutinib) is a kinase inhibitor approved for the treatment of adult patients with:
The MCL, MZL and FL indications are approved under accelerated approval based on overall response rate and durability of response. Continued approval for these indications may be contingent upon verification and description of clinical benefit in confirmatory trials.
Please see full US Prescribing Information for important information on approved uses.
For a complete list of zanubrutinib monotherapy and combination clinical trials, view the pipeline.
For a complete list of zanubrutinib monotherapy and combination clinical trials, view the pipeline or find a clinical trial.
