Description
ONO-4059 analog is a derivative of the Bruton’s tyrosine kinase (BTK) inhibitor ONO-4059 .
in vitro
ono-4059 inhibited the tmd-8 cell growth and btk phosphorylation in a concentration-dependent manner. furthermore, the decrease in btk phosphorylation subsequently down-regulated erk phosphorylation. after the combination of ono-4059 with doxorubicin, etoposide, vincristine and dexamethasone, increased apoptosis ratio was observed, 25, 20, 17 and 29%, respectively [1].
in vivo
for the 100-200 mm3 tumour groups, tumour growth inhibition at the final treatment day was 23% in qd, 72.9% in bd and 100% in dose mixed in food, groups respectively. for the 400-450 mm3 tumour groups, no growth inhibition was observed in the qd group and, growth inhibitions of 27.5% in bd and 100% in dose mixed in food were observed. the pk concentration and phosphorylated btk inhibition levels of those animals whose dose was mixed in with food were higher than that of other treatment groups [2].
IC 50
2.2 nm for btk kinase activity
References
[1] tomoko yasuhiro, toshio yoshizawa, joseph tp birkett, and kazuhito kawabata. ono-4059, a novel bruton’s tyrosine kinase (btk) inhibitor: synergistic activity in combination with chemotherapy in a abc-dlbcl cell line. 2013; blood: 122 (21): 5151 - 5151
[2] toshio yoshizawa, tomoko yasuhiro, hideyuki honda, and kazuhito kawabata. ono-4059—a potent and selective reversible bruton’s tyrosine kinase (btk) inhibitor: single agent, twice daily (bd) dosing and dosing with food results in sustained, high trough levels of ono-4059, translating into 100% tumour remission in a tmd-8 xenograft model. 2014; blood: 124 (21) 4502 - 4502
[3] simon rule, nimish shah, gilles andre salles et al. a phase i study of the oral btk inhibitor ono-4059 in patients with relapsed/refractory b-cell lymphoma. blood. 2013 122 (21): 4397 – 4397.
