Design, synthesis, and biological evaluation of a series of indolone derivatives as novel FLT3 inhibitors for the treatment of acute myeloid leukemia

被引：1

作者：

Jin, Jiaming ^{[1
]}

Cui, Zhenzhen ^{[1
]}

Lv, Cheng ^{[1
]}

Peng, Xuemei ^{[1
]}

Yan, Zhiqi ^{[1
]}

Song, Yi ^{[1
]}

Cao, Yu ^{[1
]}

Zhou, Wenyi ^{[1
]}

Wang, Enpeng ^{[1
]}

Chen, Xufan ^{[1
]}

Kang, Di ^{[1
]}

Hu, Lihong ^{[1
]}

Wang, Junwei ^{[1
]}

机构：

[1] Nanjing Univ Chinese Med, Sch Pharm, Jiangsu Key Lab Funct Subst Chinese Med, Nanjing 210023, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2023年 / 138卷

基金：

中国国家自然科学基金;

关键词：

AML; FLT3-ITD; FLT3; inhibitors; Indolone derivatives; CHEMOTHERAPY; DISCOVERY; POTENT;

D O I：

10.1016/j.bioorg.2023.106645

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

FLT3-ITD mutant has been extensively studied as a drug discovery target for acute myeloid leukemia. Based on our previous discovered FLT3 inhibitor (2), a series of urea group based indolone derivatives were designed, synthesized, and biological evaluated as novel FLT3 inhibitors for the treatment of FLT3-ITD positive AML. Among them, compound LC-3 exhibited potent inhibitory effects against FLT3 (IC50 = 8.4 nM) and significantly inhibited the proliferation of FLT3-ITD positive AML cells MV-4-11 (IC50 = 5.3 nM). In the cellular context, LC-3 strongly inhibited FLT3-mediated signaling pathways and induced cellular apoptosis by arresting cell cycle in G1 phase. In the in vivo studies, LC-3 significantly suppressed the tumor growth on MV-4-11 xenograft models (10 mg/kg/day, TGI = 92.16%) without exhibiting obvious toxicity. These results suggested that compound LC-3 might be a potential drug candidate for FLT3-ITD positive AML.

引用

页数：10

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