Chen Y, Guo Y, Zhao W, Tina Ho W-T, Fu X, Zhao Z J
Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Edmond H Fischer Signal Transduction Laboratory, College of Life Sciences, Jilin University, Changchun, China.
Oncogene. 2016 Jun 9;35(23):2971-8. doi: 10.1038/onc.2015.362. Epub 2015 Sep 28.
FLT3 internal tandem duplication (FLT3-ITD) is an activating mutation found in 20-30% of patients with acute myeloid leukemia (AML), which makes FLT3 an attractive target for the treatment of AML. Although FLT3-mutant patients respond to current FLT3 inhibitors, relapse usually happens because of the acquisition of resistant secondary mutations at the FLT3 catalytic domain, which is mainly on D835. In the search for compounds with broad FLT3 inhibition activities, we screened a kinase inhibitor library by using our unique FLT3 substrate and identified JAK3 inhibitor VI (designated JI6 hereafter) as a novel FLT3 inhibitor, which selectively targets FLT3 D835 mutants as well as FLT3-ITD. JI6 effectively inhibited FLT3-ITD-containing MV4-11 cells and HCD-57 cells transformed with FLT3-ITD and D835 mutants. Furthermore, administration of JI6 effectively targeted FLT3 signaling in vivo and suppressed the myeloproliferative phenotypes in FLT3-ITD knock-in mice, and significantly prolonged the survival of immunodeficient mice implanted with the transformed HCD-57 cells. Therefore, JI6 is a promising candidate for the development of next-generation anti-AML drugs.
FMS样酪氨酸激酶3内部串联重复（FLT3-ITD）是一种在20%-30%的急性髓系白血病（AML）患者中发现的激活突变，这使得FLT3成为治疗AML的一个有吸引力的靶点。尽管FLT3突变患者对当前的FLT3抑制剂有反应，但通常会复发，因为在FLT3催化结构域（主要是D835）获得了耐药性继发突变。在寻找具有广泛FLT3抑制活性的化合物时，我们使用独特的FLT3底物筛选了一个激酶抑制剂文库，并鉴定出JAK3抑制剂VI（以下简称JI6）为一种新型FLT3抑制剂，它能选择性地靶向FLT3 D835突变体以及FLT3-ITD。JI6有效抑制了含有FLT3-ITD的MV4-11细胞以及用FLT3-ITD和D835突变体转化的HCD-57细胞。此外，给予JI6能在体内有效靶向FLT3信号传导，并抑制FLT3-ITD基因敲入小鼠的骨髓增殖表型，显著延长植入转化的HCD-57细胞的免疫缺陷小鼠的生存期。因此，JI6是开发下一代抗AML药物的一个有前景的候选药物。
