The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia.

摘要: Purpose: Acalabrutinib (ACP-196) is a novel, potent, and highly selective Bruton tyrosine kinase (BTK) inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought evaluate antitumor effects acalabrutinib treatment two established mouse models chronic lymphocytic leukemia (CLL).Experimental Design: Two distinct were used, TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, human NSG primary CLL xenograft model. Mice received either vehicle or formulated drinking water.Results: Utilizing biochemical assays, we demonstrate that BTK inhibitor as compared with ibrutinib. In model, demonstrated on-target effects, including decreased phosphorylation PLCγ2, ERK, significant inhibition cell proliferation. Furthermore, tumor burden spleen treated was significantly vehicle-treated mice. Similarly, BTK, S6 observed. Most notably, resulted increase survival receiving vehicle.Conclusions: Treatment potently inhibits vivo, leading decreases activation key signaling molecules (including S6, ERK). complementary CLL, reduced increased treatment. Overall, showed selectivity ibrutinib while demonstrating efficacy vivo on par Clin Cancer Res; 23(11); 2831-41. ©2016 AACR.