As we know, Bruton tyrosine kinase (Btk) is a member of the TEC family kinases. In addition, it is involved in B-cell antigen receptor (BCR)-signaling pathway. Usually, BTK is expressed in all hematopoietic stem cell lineages, except for T cells. Besides, Btk is important for B cell development and function. Thence abnormal activation of BTK would lead to pathogenesis of B cell lymphomas (BCL). Therefore, BTK inhibitors are potential strategy for hematological malignancies such as CLL and BCL. For example, Zanubrutinib (BGB-3111) is a selective, orally active and covalent Btk inhibitor (IC50: 0.3 nM). Importantly, FDA has approved it for the treatment of relapsed/refractory mantle cell lymphoma (MCL).

BTK, a selective and orally active Btk inhibitor, is an antitumor agent for hematological malignancies research.

In general, Zanubrutinib inhibits BCR aggregation-triggered BTK autophosphorylation. Besides, It inhibits downstream PLC2γ signaling, and blocks cell proliferation and inhibits tumor growth.

In vitro, Zanubrutinib (72 h) inhibits a panel of MCL cell proliferation (eg: IC50: 1.487 μM, 5.884 μM for Jeko-1 and Mino CELLS). Meanwhile, Zanubrutinib (30 μM, 24 and 48 h) induces apoptosis in immortalized and primary MCL cells. In addition, Zanubrutinib (15 μM, 0-24 h) inhibits BTK autophosphorylation, AKT and GSK3 α/β activation in MCL cells.

In vivo, Zanubrutinib (2.5 and 7.5 mg/kg, p.o., BID) inhibits tumor growth in OCI-LY10 DLBCL tumor xenograft mice, with a TGI of 76% and 88% respectively. Similarly, Zanubrutinib (30 mg/kg, oral gavage, twice a day) also shows significant tumor inhibition effect in an MCL PDX model, with no detectable toxicities. Importantly, Zanubrutinib exhibits excellent pharmacokinetic properties. For example, Zanubrutinib (5 mg/kg, p.o., rats) show low clearance rate (76.8 mL/min/kg), high exposure Cmax (235 ng/mL), AUC (257 h·ng/mL), and oral bioavailability (23.6%).

In conclusion, Zanubrutinib is a selective Btk inhibitor. More importantly, Zanubrutinib shows potent antitumor effects in hematological malignancies animal model.


[1] Guo Y,et al. Discovery of Zanubrutinib (BGB-3111). J Med Chem. 2019 Sep 12;62(17):7923-7940.

[2] Li CJ, et al. Mol Cancer Ther. 2019 Feb;18(2):267-277.

[3] Rhodes JM, et al. Drug Des Devel Ther. 2021 Mar 2;15:919-926.