Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability

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成果类型：

期刊论文

作者：

Zhang, Silong;Qing, Luolong;Wang, Ziwei;Zhang, Yu;Li, Yuanyuan;...

通讯作者：

Huaxiang Fang<&wdkj&>Huan He

作者机构：

[Zhang, Silong; He, Huan] Guizhou Univ, Sch Pharmaceut Sci, Guiyang 550025, Peoples R China.

[Zhang, Silong; Wang, Ziwei; Qing, Luolong; Zhang, Yu; Liu, Yi; He, Huan] Wuhan Univ Sci & Technol, Coll Chem & Chem Engn, Key Lab Coal Convers & New Carbon Mat Hubei Prov, Wuhan 430081, Peoples R China.

[Zhang, Silong; Li, Yuanyuan; Fang, Huaxiang; He, Huan] Wuhan Yuxiang Pharmaceut Technol Co Ltd, Wuhan 430200, Peoples R China.

[Li, Yuanyuan; Liu, Yi] Wuhan Polytech Univ, Sch Life Sci & Technol, Sch Chem & Environm Engn, Wuhan 430023, Peoples R China.

[Liu, Yi] Hubei Univ Sci & Technol, Hubei Key Lab Radiat Chem & Funct Mat, Xianning, Peoples R China.

通讯机构：

[Huaxiang Fang] W

[Huan He] S

School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, P. R. China<&wdkj&>Key Laboratory of Coal Conversion and New Carbon Materials of Hubei Province, College of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, P. R. China<&wdkj&>Wuhan Yuxiang Pharmaceutical Technology Company, Limited, Wuhan 430200, P. R. China<&wdkj&>Wuhan Yuxiang Pharmaceutical Technology Company, Limited, Wuhan 430200, P. R. China

语种：

英文

期刊：

JOURNAL OF MEDICINAL CHEMISTRY

ISSN：

0022-2623

年：

2023

卷：

期：

页码：

4849-4867

DOI：

10.1021/acs.jmedchem.2c02006

基金类别：

National Natural Science Foundation of China [82204214, 22073070]; Science and Technology Plans of Tianjin [21ZYJDJC00050]

机构署名：

本校为其他机构

院系归属：

化学与环境工程学院

摘要：

Inhibition of methionine adenosyltransferase 2A (MAT2A) in cancers with a deletion of methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality, thus receiving significant interest in the field of precise cancer treatment. Herein, we report the discovery of a tetrahydrobenzo[4,5]imidazo-[1,2-a]pyrazine fragment which occupies the MAT2A allosteric pocket. The lead compound 8 exhibited extremely high potency to inhibit MAT2A enzymatic activity (IC50 = 18 nM) and proliferation of MTAP-null cancer cells (IC50 = 52 nM). 8 had a favorable pharmacokinetic profile with a bioavailabili...

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Design and Structural Optimization of Methionine Adenosyltransferase 2A (MAT2A) Inhibitors with High In Vivo Potency and Oral Bioavailability

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