Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
Department of Medicinal Chemistry, Jungwon University, Goesan, Republic of Korea.
Anticancer Res. 2021 Feb;41(2):731-737. doi: 10.21873/anticanres.14824.
BACKGROUND/AIM: FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in signal transduction underlying survival, proliferation, and differentiation of hematopoietic cells. An internal tandem duplication (ITD) in FLT3 in the juxtamembrane domain is a common mutation causing human acute myeloid leukemia (AML) and activates constitutive signaling.
We evaluated the novel FLT3 inhibitor 5-(4-fluorophenyl)-N-(naphthalen-1-yl)oxazol-2-amine (AIU2008) for the treatment of AML.
AIU2008 was designed by modifying FLT3 inhibitor 7c, and showed improved anti-leukemic efficacy in FLT3-ITD-positive AML cells. Specifically, AIU2008 inhibited cell growth and apoptotic death. In addition, AIU2008 down-regulated DNA repair genes involved in homologous recombination and non-homologous end joining. It contributed to the synergistic inhibition of AML cell growth in combination treatment with PARP inhibitors.
AIU2008 is a promising FLT3 targeting agent, and may be used in combination with PARP inhibitors for the treatment of AML.
背景/目的：FMS 样酪氨酸激酶 3（FLT3）是一种 III 类受体酪氨酸激酶，参与造血细胞的存活、增殖和分化的信号转导。FLT3 近膜结构域中的内部串联重复（ITD）是导致人类急性髓系白血病（AML）的常见突变，并激活组成型信号。
我们评估了新型 FLT3 抑制剂 5-（4-氟苯基）-N-（萘-1-基）恶唑-2-胺（AIU2008）治疗 AML 的效果。
AIU2008 通过修饰 FLT3 抑制剂 7c 设计而成，对 FLT3-ITD 阳性 AML 细胞显示出更好的抗白血病疗效。具体而言，AIU2008 抑制细胞生长和凋亡死亡。此外，AIU2008 下调了涉及同源重组和非同源末端连接的 DNA 修复基因。它与 PARP 抑制剂联合治疗可协同抑制 AML 细胞生长。
AIU2008 是一种很有前途的 FLT3 靶向药物，可能与 PARP 抑制剂联合用于治疗 AML。
