Abstract
Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as a candidate oncogene owing to its overexpression in several types of cancer. Selective PRMT4 inhibitors are useful tools for clarifying the molecular events regulated by PRMT4 and for validating PRMT4 as a therapeutic target. Here, we report the discovery of TP-064, a potent, selective, and cell-active chemical probe of human PRMT4 and its co-crystal structure with PRMT4. TP-064 inhibited the methyltransferase activity of PRMT4 with high potency (half-maximal inhibitory concentration, IC50 < 10 nM) and selectivity over other PRMT family proteins, and reduced arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155; IC50= 340 ± 30 nM) and Mediator complex subunit 12 (MED12; IC50 = 43 ± 10 nM). TP-064 treatment inhibited the proliferation of a subset of multiple myeloma cell lines, with affected cells arrested in G1 phase of the cell cycle. TP-064 and its negative control (TP-064N) will be valuable tools to further investigate the biology of PRMT4 and the therapeutic potential of PRMT4 inhibition.
Highlights
Protein arginine methyltransferases (PRMTs) catalyze arginine methylation of proteins, which involves the transfer of the methyl group of S-adenosyl-L-methionine (SAM) to the terminal guanidino nitrogens of arginine
TP-064 was developed as a small-molecule inhibitor of protein arginine methyltransferase 4 (PRMT4) (Figure 1A) by chemically optimizing seed compounds identified by high-throughput chemical library screening with a methyltransferase
We found that TP-064 inhibited the methyltransferase activity of PRMT4, with an IC50 value of < 10 nM (Figure 1B)
Summary
Protein arginine methyltransferases (PRMTs) catalyze arginine methylation of proteins, which involves the transfer of the methyl group of S-adenosyl-L-methionine (SAM) to the terminal guanidino nitrogens of arginine. PRMT4 is dysregulated in several diseases and has been linked to breast [6], prostate [9], and colorectal cancer [10] and positively regulates transcriptional activators including Wnt/β-catenin in colorectal cancer [11], estrogen receptor-α in breast cancer [12], Runt-related transcription factor 1 in myeloid leukemia [13], and the Switch/sucrose non-fermentable chromatin remodeling complex in breast cancer [14]. These reports suggest that PRMT4 is a potential therapeutic target in certain types of cancer
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