Zanubrutinib (BGB-3111) is an inhibitor of Bruton tyrosine kinase (BTK).

Ramos cells:1.8 nM, HEK293 cells:204.7 nM, OCI-LY1 cells:0.35 nM, Jurkat cells:3477 nM, BTK:0.3 nM, Sf9 cells:0.3 nM, Rec1 cells:0.36 nM, MOLM-13 cells:5095 nM, TMD8 cells:3.8 nM

In both biochemical and cellular assays, zanubrutinib demonstrated nanomolar BTK inhibition activity. In several MCL and DLBCL cell lines, zanubrutinib inhibited BCR aggregation-triggered BTK autophosphorylation, blocked downstream PLC-γ2 signaling, and potently inhibited cell proliferation. In comparison with ibrutinib, zanubrutinib showed much more restricted off-target activities against a panel of kinases, including ITK. While ibrutinib significantly inhibited rituximab-induced NK cell IFN-γ secretion and in vitro cytotoxicity on mantle cell lymphoma cells, zanubrutinib was at least 10-fold weaker than ibrutinib in inhibiting rituximab induced ADCC, consistent with its weak ITK inhibition activity[1].

In mouse BTK occupancy assays, treatment with zanubrutinib resulted in a dose-dependent BTK occupancy and showed about 3-fold more potency than ibrutinib in target organs, including PBMC and spleen.zanubrutinib induced dose-dependent anti-tumor effects against REC-1 MCL xenografts engrafted either subcutaneously or systemically via tail vein injection in mice.In the subcutaneous xenografts, zanubrutinib at 2.5 mg/kg BID showed similar activity as ibrutinib at 50 mg/kg QD, its clinical relevant dose.In the systemic model, the median survival of zanubrutinib 25 mg/kg BID group was significantly longer than those of both ibrutinib 50 mg/kg QD and BID groups.In an ABC-subtype DLBCL (TMD-8) subcutaneous xenograft model, zanubrutinib also demonstrated better anti-tumor activity than ibrutinib.Preliminary 14-day toxicity study in rats showed that zanubrutinib was very well tolerated and maximal tolerate dose (MTD) was not reached when it was dosed up to 250mg/kg/day[1].