文章：

Pacritinib (SB1518)，一种用于治疗急性髓性白血病的JAK2/FLT3抑制剂

Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia

原文发布日期：2011-11-11

DOI: 10.1038/bcj.2011.43

类型: Original Article

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英文摘要：

FMS-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene found in acute myeloid leukemia (AML) patients and its activating mutations have been proven to be a negative prognostic marker for clinical outcome. Pacritinib (SB1518) is a tyrosine kinase inhibitor (TKI) with equipotent activity against FLT3 (IC50=22 nM) and Janus kinase 2 (JAK2, IC50=23 nM). Pacritinib inhibits FLT3 phosphorylation and downstream STAT, MAPK and PI3 K signaling in FLT3-internal-tandem duplication (ITD), FLT3-wt cells and primary AML blast cells. Oral administration of pacritinib in murine models of FLT3-ITD-driven AML led to significant inhibition of primary tumor growth and lung metastasis. Upregulation of JAK2 in FLT3-TKI-resistant AML cells was identified as a potential mechanism of resistance to selective FLT3 inhibition. This resistance could be overcome by the combined FLT3 and JAK2 activities of pacritinib in this cellular model. Our findings provide a rationale for the clinical evaluation of pacritinib in AML including patients resistant to FLT3-TKI therapy.

摘要翻译： 

FMS样酪氨酸激酶3（FLT3）是急性髓系白血病（AML）患者中最常见的突变基因，其激活突变已被证实是临床预后的负面标志物。帕克替尼（SB1518）是一种酪氨酸激酶抑制剂（TKI），对FLT3（IC50=22 nM）和Janus激酶2（JAK2，IC50=23 nM）具有同等强度的抑制活性。在FLT3内部串联重复（ITD）、FLT3野生型细胞及原代AML母细胞中，帕克替尼能抑制FLT3磷酸化及下游STAT、MAPK和PI3K信号通路。在FLT3-ITD驱动的AML小鼠模型中口服帕克替尼，可显著抑制原发性肿瘤生长和肺转移。研究发现，FLT3-TKI耐药AML细胞中JAK2的上调是导致选择性FLT3抑制耐药的可能机制。在该细胞模型中，帕克替尼通过协同抑制FLT3和JAK2活性可克服此类耐药。我们的研究为帕克替尼在AML（包括对FLT3-TKI治疗耐药的患者）中的临床评估提供了理论依据。

原文链接：

Pacritinib (SB1518), a JAK2/FLT3 inhibitor for the treatment of acute myeloid leukemia