A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors

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成果类型：

期刊论文

作者：

Deng, Youchao;Song, Xiaosheng;Iyamu, Iredia D.;Dong, Aiping;Min, Jinrong;...

通讯作者：

Huang, R;Min, JR

作者机构：

[Huang, Rong; Deng, Youchao; Iyamu, Iredia D.] Purdue Univ, Inst Drug Discovery, Ctr Canc Res, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA.

[Dong, Aiping; Min, Jinrong; Song, Xiaosheng] Univ Toronto, Dept Physiol, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada.

[Dong, Aiping; Min, Jinrong; Song, Xiaosheng] Univ Toronto, Dept Physiol, Toronto, ON M5G 1L7, Canada.

[Min, Jinrong] Cent China Normal Univ, Sch Life Sci, Hubei Key Lab Genet Regulat & Integrat Biol, Wuhan 430079, Peoples R China.

[Deng, Youchao] Cent South Univ, Xiangya Sch Pharmaceut Sci, Changsha 410013, Peoples R China.

通讯机构：

[Huang, R ] P

[Min, JR ] U

Purdue Univ, Inst Drug Discovery, Ctr Canc Res, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA.

Univ Toronto, Dept Physiol, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada.

Univ Toronto, Dept Physiol, Toronto, ON M5G 1L7, Canada.

语种：

英文

关键词：

PRMTs;Structure based inhibitor design;Benzyl urea;Noncanonical SAH mimic;Homocysteine binding pocket;Crystal structure

期刊：

药学学报(英文)

ISSN：

2211-3835

年：

2023

卷：

期：

页码：

4893-4905

DOI：

10.1016/j.apsb.2023.07.022

基金类别：

AbbVie; Bayer Pharma AG; Canada Foundation for Innovation; Genome Canada through Ontario Ge-nomics Institute [OGI-055]; Innovative Medicines Initiative (EU/EFPIA) [115766]; Janssen; Merck KGaA, Darmstadt, Germany; Ontario Ministry of Research, Innovation and Science (MRIS); Pfizer; So Paulo Research Foundation-FAPESP; Takeda; Well-come; Purdue University Faculty Scholar program from the Ralph W. and Grace M. Showalter Trust; Department of Medicinal Chemistry and Molecular Pharmacology; NIH [P30 CA023168]; NSERC [RGPIN-2021-02728]

机构署名：

本校为通讯机构

院系归属：

生命科学学院

摘要：

Protein arginine methyltransferases (PRMTs) are attractive targets for developing therapeutic agents, but selective PRMT inhibitors targeting the cofactor SAM binding site are limited. Herein, we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea, potently and selectively inhibiting PRMT3/4/5. Importantly, crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4, providing a structural basis for the selectivity. In addition...

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A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors

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