Discovery and Rational Design of Pteridin-7(8H)-one-Based Inhibitors Targeting FMS-like Tyrosine Kinase 3 (FLT3) and Its Mutants

被引：27

作者：

Sun, Deheng ^{[1
]}

Yang, Yu ^{[1
]}

Lyu, Jiankun ^{[1
]}

Zhou, Wei ^{[1
]}

Song, Wenlin ^{[1
]}

Zhao, Zhenjiang ^{[1
]}

Chen, Zhuo ^{[1
]}

Xu, Yufang ^{[1
]}

Li, Honglin ^{[1
]}

机构：

[1] E China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 13期

基金：

中国国家自然科学基金;

关键词：

ACUTE MYELOID-LEUKEMIA; ACTIVATION LOOP; RESISTANCE; MUTATIONS; CRENOLANIB; SENSITIVITY; LIGAND; AML;

D O I：

10.1021/acs.jmedchem.6b00374

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 G(0)/G(1) 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.

引用

页码：6187 / 6200

页数：14

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