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

作　　者：Youchao Deng Xiaosheng Song Iredia D.Iyamu Aiping Dong Jinrong Min Rong Huang 

机构地区：[1]Department of Medicinal Chemistry and Molecular Pharmacology,Center for Cancer Research,Institute for Drug Discovery,Purdue University,West Lafayette,IN 47907,USA [2]Structural Genomics Consortium and Department of Physiology,University of Toronto,Toronto,Ontario M5G 1L7,Canada [3]Hubei Key Laboratory of Genetic Regulation and Integrative Biology,School of Life Sciences,Central China Normal University,Wuhan 430079,China [4]Xiangya School of Pharmaceutical Sciences,Central South University,Changsha 410013,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第12期4893-4905,共13页药学学报（英文版）

基　　金：support from NIH P30 CA023168(Purdue University Center for Cancer Research);the NSERC grant(RGPIN-2021-02728(Jinrong Min)).

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,YD1113 can be modified by introducing a substrate mimic to form a“T-shaped”bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets,exhibiting potent and selective inhibition to typeⅠPRMTs(IC_(50)<5 nmol/L).In summary,we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.

关 键 词：PRMTs Structure based inhibitor design Benzyl urea Noncanonical SAH mimic Homocysteine binding pocket Crystal structure 

分 类 号：R914[医药卫生—药物化学]