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)

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Summary

Introduction

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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