BPR1J373, an oral multiple tyrosine kinase inhibitor, targets c-KIT for the treatment of c-KIT-driven myeloid leukemia

Li Tzong Chen, Chiung Tong Chen, Weir Torn Jiaang, Tsai Yun Chen, Joseph H. Butterfield, Neng Yao Shih, John Tsu An Hsu, Hui You Lin, Sheng Fung Lin, Hui Jen Tsai

研究成果: Article同行評審

8 引文 斯高帕斯(Scopus)

摘要

Acute myelogenous 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 gastrointestinal 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 the 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 antitumor response of BPR1J373 was also shown in subcutaneously grafted SCID 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 clinical use in c-KIT-driven myeloid leukemia.

原文English
頁(從 - 到)2323-2333
頁數11
期刊Molecular cancer therapeutics
15
發行號10
DOIs
出版狀態Published - 2016 十月

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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