MS049 is a Selective and Dual Inhibitor of PRMT4 and PRMT6

Protein arginine N-methyltransferase 4 (PRMT4) methylation of arginine residues in proteins plays a key role in transcriptional regulation. Specifically, PRMT4 binds to transcription activators called p160 and CBP/P300. Besides, the modified forms of these proteins are involved in the stimulation of gene expression through steroid hormone receptors. Moreover, PRMT4 methylated core histones H3 and H4. They are also targets for histone acetylase activity of CBP/P300 coactivators. Furthermore, PRMT4 can recruit chromatin by binding with coactivators, which can increase histone methylation and enhance the transcriptional accessibility of the promoter region. The methylation of transcription coactivator CBP by PRMT4 inhibits the binding of CREB, thus allocating a limited pool of CBP cells to steroid receptor interactions.

Meanwhile, PRMT6 is a type I PRMT and oncogene. PRMT6 inhibits p53, p21, and p16, which are relevant to cell cycle arrest and apoptosis. Nonetheless, PRMT6 is overexpressed in breast cancer, prostate cancer, bladder cancer, and lung cancer. In cancer, higher levels of PRMT6 predict a better prognosis. PRMT6 is an important cell regulator of the PTEN-Akt axis. Here, we will introduce a selective dual inhibitor of PRMT4 and PRMT6, MS049.

MS049 is a Selective and Dual Inhibitor of PRMT4 and PRMT6.

At first, MS049 is a potent, selective, and cell-active dual inhibitor of PRMT4 and PRMT6 with IC₅₀s of 34 nM and 43 nM, respectively. Particularly, MS049 reduces levels of Med12me2a and H3R2me2a in HEK293 cells. Obviously, MS049 is not toxic and does not affect the growth of HEK293 cells.

Secondly, MS049 reduces the H3R2me2a mark in HEK293 cells in a concentration-dependent manner (IC₅₀=0.97 μM). Importantly, MS049 with 0.1-100 μM for 72 hours inhibits endogenous PRMT4 methyltransferase activity in a concentration-dependent manner. Interestingly, it results in reduced levels of cellular asymmetric arginine dimethylation of Med12 (Med12-Rme2a, IC₅₀=1.4 μM) in HEK293 cells.

Thirdly, MS049 is selective for PRMT4 and PRMT6 over a broad range of epigenetic modifiers. Additionally, they include other PRMTs, PKMTs, DNMTs, KDMs, and methyllysine/methylarginine reader proteins, and non-epigenetic targets

Finally, MS049 is a potent, selective, and cell-active dual inhibitor of PRMT4 and PRMT6.

References:

Shen Y et al. J Med Chem. 2016 Oct 13;59(19):9124-9139.