MS049 is a dual inhibitor of PRMT4 and PRMT6

**Background**

Protein arginine methyltransferases (PRMTs) play a critical role in the regulation of gene expression by catalyzing the transfer of methyl groups to arginine residues on various proteins, including histones. Among these, PRMT4 (CARM1) and PRMT6 are Type I PRMTs that primarily catalyze the formation of asymmetric dimethylarginine (ADMA). These epigenetic modifications are essential for modulating chromatin structure and transcriptional activity, and their dysregulation is frequently implicated in various diseases, including cancer. Given the importance of these enzymes in maintaining cellular homeostasis and their role in oncogenic signaling, the development of selective chemical probes to inhibit their activity is of great research significance. In this context, we will introduce a potent dual inhibitor of PRMT4 and PRMT6 – MS049.

**Definition**

MS049 is a potent, selective, and cell-active dual inhibitor of PRMT4 and PRMT6, exhibiting IC50 values of 34 nM and 43 nM, respectively.

**In Vitro Studies**

According to the MS049 description, this chemical probe is highly selective for PRMT4 and PRMT6 over a broad range of other epigenetic modifiers, including other PRMTs, PKMTs, DNMTs, KDMs, and methyllysine/methylarginine reader proteins. In terms of MS049 biological activity, in vitro studies in HEK293 cells demonstrated that MS049 (0.1-10 μM; 20 hours) reduces the H3R2me2a mark in a concentration-dependent manner with an IC50 of 0.97±0.05 μM. Furthermore, treatment with MS049 (0.1-100 μM; 72 hours) inhibits endogenous PRMT4 methyltransferase activity, resulting in reduced levels of cellular asymmetric arginine dimethylation of Med12 (Med12-Rme2a) with an IC50 of 1.4±0.1 μM. Notably, MS049 is not toxic and does not affect the growth of HEK293 cells, making it a valuable tool for studying MS049 epigenetics. In conclusion, MS049 is a potent and selective dual inhibitor of PRMT4 and PRMT6 that effectively reduces the levels of Med12me2a and H3R2me2a in cellular environments.

Keywords

MS049, 1502816-23-0, MS 049, MS-049, Histone Methyltransferase, epigenetic, modifiers, selective, arginine, dimethylation, toxic, H4R3me2a, HEK293, cells, Inhibitor

References

[1] Shen Y et al. Discovery of a Potent, Selective, and Cell-Active Dual Inhibitor of Protein Arginine Methyltransferase 4 and Protein Arginine Methyltransferase 6. J Med Chem. 2016 Sep 15.