title: BPR1J373, an Oral Multiple Tyrosine Kinase Inhibitor, Targets c-KIT for the Treatment of c-KIT-Driven Myeloid Leukemia.
abstract: 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.
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan. Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan. Division of Hematology/Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Institute of Molecular Medicine, National Cheng Kung University, Tainan, Taiwan.
authors: Li-Tzong
authors: LT
authors: Chen
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors: Chiung-Tong
authors: CT
authors: Chen
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors: Weir-Torn
authors: WT
authors: Jiaang
authors: Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors: Tsai-Yun
authors: TY
authors: Chen
authors: Division of Allergic Diseases, Mayo Clinic, Rochester, Minnesota.
authors: Joseph H
authors: JH
authors: Butterfield
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors: Neng-Yao
authors: NY
authors: Shih
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors: John Tsu-An
authors: JT
authors: Hsu
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
authors: Hui-You
authors: HY
authors: Lin
authors: Division of Hematology/Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Sheng-Fung
authors: SF
authors: Lin
authors: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan. Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan. Division of Hematology/Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. hjtsai@nhri.org.tw.
authors: Hui-Jen
authors: HJ
authors: Tsai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation; D014178:Translocation, Genetic; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit