title: Evaluation of the antitumor effects of BPR1J-340, a potent and selective FLT3 inhibitor, alone or in combination with an HDAC inhibitor, vorinostat, in AML cancer.
abstract: Overexpression or/and activating mutation of FLT3 kinase play a major driving role in the pathogenesis of acute myeloid leukemia (AML). Hence, pharmacologic inhibitors of FLT3 are of therapeutic potential for AML treatment. In this study, BPR1J-340 was identified as a novel potent FLT3 inhibitor by biochemical kinase activity (IC50 approximately 25 nM) and cellular proliferation (GC50 approximately 5 nM) assays. BPR1J-340 inhibited the phosphorylation of FLT3 and STAT5 and triggered apoptosis in FLT3-ITD(+) AML cells. The pharmacokinetic parameters of BPR1J-340 in rats were determined. BPR1J-340 also demonstrated pronounced tumor growth inhibition and regression in FLT3-ITD(+) AML murine xenograft models. The combination treatment of the HDAC inhibitor vorinostat (SAHA) with BPR1J-340 synergistically induced apoptosis via Mcl-1 down-regulation in MOLM-13 AML cells, indicating that the combination of selective FLT3 kinase inhibitors and HDAC inhibitors could exhibit clinical benefit in AML therapy. Our results suggest that BPR1J-340 may be further developed in the preclinical and clinical studies as therapeutics in AML treatments.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Teng-Kuang
authors.initials: TK
authors.lastname: Yeh
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Weir-Torn
authors.initials: WT
authors.lastname: Jiaang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Kuei-Jung
authors.initials: KJ
authors.lastname: Yen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Chun-Hwa
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Chin-Ting
authors.initials: CT
authors.lastname: Huang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Yen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Hsieh
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Ling-Hui
authors.initials: LH
authors.lastname: Chou
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Chun-Hsien
authors.initials: CH
authors.lastname: Chiu
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Li-Chun
authors.initials: LC
authors.lastname: Kao
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan ; Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000077337:Vorinostat; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C000591312:BPR1J-340; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D047428:Protein Kinase Inhibitors; D000077337:Vorinostat; D014508:Urea; D051941:fms-Like Tyrosine Kinase 3