FLT3 has been validated as a therapeutic target for the treatment of acute myeloid leukemia (AML). In this paper, we describe for the first time, pteridin-7(8H)-one as a scaffold for potent FLT3 inhibitors derived from structural optimizations on irreversible EGFR inhibitors. The representative inhibitor (31) demonstrates single-digit nanomolar inhibition against FLT3 and subnanomolar K_D for drug-resistance FLT3 mutants. In profiling of the in vitro tumor cell lines, it shows good selectivity against AML cells harboring FLT3-ITD mutations over other leukemia and solid tumor cell lines. The mechanism of action study illustrates that pteridin-7(8H)-one derivatives suppress the phosphorylation of FLT3 and its downstream pathways, thereby inducing G₀/G₁ cell cycle arrest and apoptosis in AML cells. In in vivo studies, 31 significantly suppresses the tumor growth in MV4–11 xenograft model. Overall, we provide a structurally distinct chemical scaffold with which to develop FLT3 mutants-selective inhibitors for AML treatment.

中文翻译：

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靶向FMS样酪氨酸激酶3（FLT3）及其突变体的基于Pteridin-7（8 H）-一的抑制剂的发现和合理设计

FLT3已被确认为治疗急性髓细胞性白血病（AML）的治疗靶标。在本文中，我们首次描述了蝶呤7（8 H）-one作为有效的FLT3抑制剂的支架，该抑制剂来自不可逆EGFR抑制剂的结构优化。代表性的抑制剂（31）表现出对FLT3和耐药性FLT3突变体的纳摩尔摩尔数K _D的个位数纳摩尔抑制作用。在体外肿瘤细胞系的概况分析中，与其他白血病和实体瘤细胞系相比，它对具有FLT3-ITD突变的AML细胞显示出良好的选择性。作用机理的研究表明，蝶呤7（8 H-一衍生物抑制FLT3及其下游途径的磷酸化，从而诱导AML细胞中G ₀ / G ₁细胞周期停滞和凋亡。在体内研究中，31在MV4-11异种移植模型中显着抑制了肿瘤的生长。总体而言，我们提供了结构上独特的化学支架，可利用其开发用于AML治疗的FLT3突变体-选择性抑制剂。