1. 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.
- Author
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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, and Hsu, John T.-A.
- Subjects
ANTINEOPLASTIC agents ,HISTONE deacetylase inhibitors ,ACUTE myeloid leukemia ,GENETIC mutation ,CELL proliferation ,CELLULAR signal transduction - 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 (IC
50 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. [ABSTRACT FROM AUTHOR]- Published
- 2014
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