Discovery of 2-Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities

被引：5

作者：

Li, Xuemei ^{[1
]}

Wang, Peipei ^{[2
]}

Wang, Chang ^{[3
]}

Jin, Tingting ^{[4
]}

Xu, Ran ^{[2
]}

Tong, Lexian ^{[1
,5
]}

Hu, Xiaobei ^{[3
,6
]}

Shen, Liteng ^{[7
]}

Li, Jia ^{[2
,3
,6
]}

Zhou, Yubo ^{[2
,3
,6
]}

Liu, Tao ^{[1
,7
]}

机构：

[1] Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China

[2] Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

[4] Zhejiang Univ, Affiliated Hangzhou Peoples Hosp 1, Sch Med Hangzhou,Key Lab Clin Canc Pharmacol & Tox, Dept Clin Pharm, Hangzhou 310006, Peoples R China

[5] Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou 310018, Peoples R China

[6] Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Guangdong, Peoples R China

[7] Zhejiang Univ, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Hangzhou 310058, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 17期

基金：

中国国家自然科学基金;

关键词：

BACTERIAL TOPOISOMERASE INHIBITORS; FLT3; P53; RESISTANCE; MUTATIONS; DESIGN;

D O I：

10.1021/acs.jmedchem.3c00245

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

FLT3 inhibitors as single agents have limited effectsbecause ofacquired and adaptive resistance and the cardiotoxicity related tohuman ether-a-go-go-related gene (hERG) channel blockade further impedessafe drugs to the market. Inhibitors having potential to overcomeresistance and reduce hERG affinity are highly demanded. Here, wereported a dual FLT3/CHK1 inhibitor 18, which displayedpotencies to overcome varying acquired resistance in BaF3 cells withFLT3-TKD and FLT3-ITD-TKD mutations. Moreover, 18 displayedhigh selectivity over c-KIT more than 1700-fold and greatly reducedhERG affinity, with an IC50 value of 58.4 & mu;M. Furthermechanistic studies demonstrated 18 can upregulate p53and abolish the outgrowth of adaptive resistant cells. In the in vivostudies, 18 demonstrated favorable PK profiles and goodsafety, suppressed the tumor growth in the MV-4-11 cell inoculatedmouse xenograft model, and prolonged the survival in the Molm-13 transplantationmodel, supporting its further development.

引用

页码：11792 / 11814

页数：23

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