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