Protein arginine methyltransferases(PRMTs)have been implicated in the progression of many diseases.Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inh...Protein arginine methyltransferases(PRMTs)have been implicated in the progression of many diseases.Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery.Herein,we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a S-adenosylmethionine(SAM)analogue moiety and a tripeptide through an alkyl substituted guanidino group.Compound AH237 is a potent and selective inhibitor for PRMT4 and PRMT5 with a half-maximal inhibition concentration(IC_(50)) of 2.8 and0.42 nmol/L,respectively.Computational studies provided a plausible explanation for the high potency and selectivity of AH237 for PRMT4/5 over other 40 methyltransferases.This proof-of-principle study outlines an applicable strategy to develop potent and selective bisubstrate inhibitors for PRMTs,providing valuable probes for future structural studies.展开更多
基金support from National Institute of Health(NIH)grants R01GM117275(RH)P30 CA023168(Purdue University Center for Cancer Research,West Lafayette,IN,USA)
文摘Protein arginine methyltransferases(PRMTs)have been implicated in the progression of many diseases.Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery.Herein,we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a S-adenosylmethionine(SAM)analogue moiety and a tripeptide through an alkyl substituted guanidino group.Compound AH237 is a potent and selective inhibitor for PRMT4 and PRMT5 with a half-maximal inhibition concentration(IC_(50)) of 2.8 and0.42 nmol/L,respectively.Computational studies provided a plausible explanation for the high potency and selectivity of AH237 for PRMT4/5 over other 40 methyltransferases.This proof-of-principle study outlines an applicable strategy to develop potent and selective bisubstrate inhibitors for PRMTs,providing valuable probes for future structural studies.
