標題: 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
作者: Lin, Wen-Hsing
Yeh, Teng-Kuang
Jiaang, Weir-Torn
Yen, Kuei-Jung
Chen, Chun-Hwa
Huang, Chin-Ting
Yen, Shih-Chieh
Hsieh, Shu-Yi
Chou, Ling-Hui
Chen, Ching-Ping
Chiu, Chun-Hsien
Kao, Li-Chun
Chao, Yu-Sheng
Chen, Chiung-Tong
Hsu, John T. -A.
生物科技學系
Department of Biological Science and Technology
公開日期: 8-Jan-2014
摘要: 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 (GC(50) 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.
URI: http://dx.doi.org/10.1371/journal.pone.0083160
http://hdl.handle.net/11536/23599
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0083160
期刊: PLOS ONE
Volume: 9
Issue: 1
結束頁: 
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