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

• Published in: Molecular cancer therapeutics 2016-10, Vol.15 (10), p.2323-2333
• Main Authors: Chen, Li-Tzong, Chen, Chiung-Tong, Jiaang, Weir-Torn, Chen, Tsai-Yun, Butterfield, Joseph H, Shih, Neng-Yao, Hsu, John Tsu-An, Lin, Hui-You, Lin, Sheng-Fung, Tsai, Hui-Jen
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Models, Animal; Humans; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Male; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mutation; Phosphorylation; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-kit - antagonists & inhibitors; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Signal Transduction - drug effects; Transcriptional Activation; Translocation, Genetic; Tumor Burden - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-15-1006

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. Mol Cancer Ther; 15(10); 2323-33. ©2016 AACR.