Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, No. 35, Keyan Road, Zhunan, Miaoli County 350, Taiwan.
Br J Cancer. 2012 Jan 31;106(3):475-81. doi: 10.1038/bjc.2011.564. Epub 2011 Dec 20.
Activating mutations of Fms-like tyrosine kinase 3 (FLT3) constitute a major driver in the pathogenesis of acute myeloid leukaemia (AML). Hence, pharmacological inhibitors of FLT3 are of therapeutic interest for AML.
The effects of inhibition of FLT3 activity by a novel potent FLT3 inhibitor, BPR1J-097, were investigated using in vitro and in vivo assays.
The 50% inhibitory concentration (IC(50)) of BPR1J-097 required to inhibit FLT3 kinase activity ranged from 1 to 10 nM, and the 50% growth inhibition concentrations (GC(50)s) were 21±7 and 46±14 nM for MOLM-13 and MV4-11 cells, respectively. BPR1J-097 inhibited FLT3/signal transducer and activator of transcription 5 phosphorylation and triggered apoptosis in FLT3-driven AML cells. BPR1J-097 also showed favourable pharmacokinetic property and pronounced dose-dependent tumour growth inhibition and regression in FLT3-driven AML murine xenograft models.
These results indicate that BPR1J-097 is a novel small molecule FLT-3 inhibitor with promising in vivo anti-tumour activities and suggest that BPR1J-097 may be further developed in preclinical and clinical studies as therapeutics in AML treatments.
Fms 样酪氨酸激酶 3（FLT3）的激活突变构成了急性髓系白血病（AML）发病机制的主要驱动因素。因此，FLT3 的药理学抑制剂对 AML 具有治疗意义。
使用体外和体内测定法研究了新型强效 FLT3 抑制剂 BPR1J-097 对 FLT3 活性的抑制作用。
BPR1J-097 抑制 FLT3 激酶活性的 50%抑制浓度（IC50）范围为 1 至 10 nM，对 MOLM-13 和 MV4-11 细胞的 50%生长抑制浓度（GC50）分别为 21±7 和 46±14 nM。BPR1J-097 抑制了 FLT3/信号转导和转录激活因子 5 的磷酸化，并触发了 FLT3 驱动的 AML 细胞凋亡。BPR1J-097 还表现出良好的药代动力学特性，并在 FLT3 驱动的 AML 小鼠异种移植模型中表现出明显的剂量依赖性肿瘤生长抑制和消退。
这些结果表明，BPR1J-097 是一种新型的小分子 FLT-3 抑制剂，具有有前途的体内抗肿瘤活性，并表明 BPR1J-097 可能在临床前和临床研究中进一步开发为 AML 治疗的治疗药物。
