tirabrutinib(ONO-4059) hydrochloride

ONO-4059 covalently binds to BTK, and reversibly blocks BCR signaling and B-cell proliferation and activation^[1]. It has greater selectivity for BTK than Lck, Fyn, LynA and ONO/GS-4059 only inhibits anti-IgM-induced B-cell activation in a concentration-dependent manner but not inhibit anti-CD3/CD28-induced activation of T-lymphocytes from human PBMCs. ONO/GS-4059 inhibits cell proliferation in some malignant B-cell lines but also induces classical apoptosis at nanomolar concentration in the activated-B cell (ABC) DLBCL cell line, TMD8^[4].

ONO-4059 demonstrates therapeutic efficacy in a mouse CIA model by suppressing generation of inflammatory chemokines and cytokines including IL-6, IL-8, and TNFα by monocytes, and accompanied by regression of cartilage erosion, bone damage, and pannus formation^[1]. In pre-clinical models, and in the clinic in both CLL and NHL patients, It exerts its anti-tumour activity, with a favourable safety profile along with promising efficacy over a long duration^[3].

• Cell lines

  DLBCL cell lines TMD8 cells

• Concentrations

  320 nM

• Incubation Time

  48 h

• Method

  Cells are treated with420 nM, ONO/GS-4059 (320 nM) or in combination for 48 hours and apoptosis is assessed by FITC Annexin V staining, and measured by flow cytometry

• Animal Models

  Male CB17-SCID mice

• Dosages

  5 and 10 mg/kg

• Administration

  by oral gavage