文章：

新型酪氨酸激酶抑制剂AKN-028在急性髓系白血病细胞系和原代培养物中具有显著的抗白血病活性

The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia

原文发布日期：2012-08-03

DOI: 10.1038/bcj.2012.28

类型: Original Article

开放获取: 是

英文摘要：

Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nM), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μM). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).

摘要翻译： 

异常表达的酪氨酸激酶已成为急性髓系白血病（AML）药物开发中极具前景的靶点。我们报道新型酪氨酸激酶抑制剂（TKI）AKN-028是一种强效FMS样酪氨酸激酶3（FLT3）抑制剂（IC50=6 nM），可剂量依赖性抑制FLT3自身磷酸化。在过表达KIT的人巨核细胞白血病细胞系中，AKN-028显示出对KIT自身磷酸化的抑制作用。在17种细胞系组成的测试组中，AKN-028对所有五种AML细胞系均表现出细胞毒活性。该化合物通过激活caspase 3诱导MV4-11细胞凋亡。在原发性AML样本（n=15）中，AKN-028诱导了明显的剂量依赖性细胞毒反应（平均IC50为1 μM），但抗白血病活性与FLT3突变状态或FLT3定量表达水平无相关性。联合用药研究表明，当阿糖胞苷或柔红霉素与AKN-028同时给药或提前24小时给药时，可产生协同效应。在小鼠模型中，AKN-028对原发性AML和MV4-11细胞均表现出高口服生物利用度和抗白血病效应，且实验期间未观察到主要毒性反应。综上所述，AKN-028是一种在临床前研究中具有显著抗AML活性的新型TKI，其与标准AML药物可能存在的序贯协同效应及良好口服生物利用度，使其成为临床试验（进行中）的候选药物。

原文链接：

The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia