BPR1J373, an Oral Multiple Tyrosine Kinase Inhibitor, Targets c-KIT for the Treatment of c-KIT–Driven Myeloid Leukemia

摘要

[[abstract]]Acute myeloid leukemia (AML) carrying t(8;21)(q22;q22) or inv(16)/t(16;16)(p13;q22) is classified as core binding factor (CBF)-AML and accounts for approximately 15% of AML. C-KIT mutation can be detected in 17~46% of CBF-AML and is associated with poor prognosis. C-KIT mutation is a crucial hit and cooperates with AML1-ETO resulting from t(8;21)(q22;q22) to cause overt AML. Tyrosine kinase inhibitors (TKI) targeting c-KIT, such as imatinib, has been used successfully to treat c-KIT driven gastro-intestinal stromal tumors. However the effect of TKI on c-KIT driven leukemia, including CBF-AML and systemic mastocytosis (SM), has not been satisfactory. BPR1J373 is a 5-phenylthiazol-2-ylamine-pyriminide derivative targeting multiple tyrosine kinases. It was shown to inhibit cell proliferation and induce apoptosis in AML cells with constitutively activated c-KIT via inhibiting c-KIT phosphorylation and its downstream signals. The compound induced apoptosis by mitochondrial intrinsic pathway through upregulation of proapoptotic proteins Bax and Bak and caspase 8 and 9 activation in c-KIT mutant Kasumi-1 cells. Furthermore, it induced cell cycle arrest via targeting aurora kinase B in c-KIT wild type KG-1 cells. The anti-tumor response of BPR1J373 was also shown in subcutaneously grafted SICD mice. BPR1J373 was shown to effectively suppress c-KIT phosphorylation of D816V mutation by treating c-KIT-null COS-1 cells transfected with c-KIT D816V mutant plasmid. In conclusion, BPR1J373 inhibits cell proliferation of c-KIT driven AML cells via induction of apoptosis and cell cycle arrest. It is also effective for multiple drug resistant c-KIT D816V mutation. BPR1J373 deserves further development for the clinical use in c-KIT driven myeloid leukemia.