PT  - JOURNAL ARTICLE
AU  - Ayad A. Al-Hamashi
AU  - Dongxing Chen
AU  - Youchao Deng
AU  - Guangping Dong
AU  - Rong Huang
TI  - Discovery of a Potent and Dual-Selective Bisubstrate Inhibitor for Protein Arginine Methyltransferase 4/5
AID  - 10.1101/2020.09.05.283978
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.05.283978
4099  - http://biorxiv.org/content/early/2020/09/06/2020.09.05.283978.short
4100  - http://biorxiv.org/content/early/2020/09/06/2020.09.05.283978.full
AB  - 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 (IC50) of 2.8 nM and <1.5 nM, 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.Competing Interest StatementThe authors have declared no competing interest.