Pharmacophore-Based Virtual Screening and Biological Evaluation of Small Molecule Inhibitors for Protein Arginine Methylation

Abstract

Protein arginine methyltransferases (PRMTs) are proved to play vital roles in chromatin remodeling, RNA metabolism and signal transduction. Aberrant regulation of PRMT activity is associated with various pathological states such as cancer and cardiovascular disorders. Development and application of small molecule PRMT inhibitors will provide new avenues for therapeutic discovery. We combined pharmacophore-based virtual screening methods with radioactive methylation assays, six hits were identified as inhibitors against the predominant arginine methyltransferase PRMT1 within micromolar potency. Two potent compounds, A9 and A36, exhibitting the inhibitory effect by directly targeting substrate H4 other than PRMT1 and displayed even higher inhibition activity than the well-known PRMT inhibitors AMI-1 and stilbamidine. A9 significantly inhibits proliferation of castrate-resistant prostate cancer cells. Together, A9 may be a potential inhibitor against advanced hormone-independent cancers and the work will provide clues for the future development of specific compounds that block the interaction of PRMTs with their targets.

Arginine Methyltransferase 1 in the Nucleus Accumbens Regulates Behavioral Effects of Cocaine

“…Moreover, rattus norvegicus PRMT3 (rPRMT3; PDB code 1F3L) and hPRMT3 (PDB code 3SMQ) structures are established. Since sequence alignments show that mPRMT1 and hPRMT1 are exactly the same within the binding pocket, we built a homology model of hPRMT1 (Zhang and Cheng, 2003;Yan et al, 2014) to process the virtual screening (see Fig. 4B).…”

“…Similar to the discovery of other novel small-molecule inhibitors (Knutson et al, 2012;Lobera et al, 2013), a virtual screening against an in-house database (15,039 compounds) was first performed (see Materials and Methods). The first few hundred hits were clustered and visually inspected in consideration of the binding mode of known inhibitors of PRMT1 Bissinger et al, 2011;Cheng et al, 2011;Wang et al, 2012a).…”

“…Recent studies and functional analyses indicate that PRMT1 is highly regulated in the brain in response to external stimuli, and that it is likely essential to varied brain functions (Birkaya and Aletta, 2005;Miyata et al, 2008;Wang et al, 2012b). For example, knockdown of PRMT1 reduces H4R3me2a levels, while decreasing proliferation and enhancing apoptosis in cells derived from glioma lines (Wang et al, 2012b).…”

“…For example, knockdown of PRMT1 reduces H4R3me2a levels, while decreasing proliferation and enhancing apoptosis in cells derived from glioma lines (Wang et al, 2012b). Moreover, PRMT1 is activated by nerve growth factor and may contribute to the activation of specific plasticity-related signal transduction pathways (Birkaya and Aletta, 2005).…”

Discovery and structure–activity analysis of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives as novel protein arginine methyltransferase 1 (PRMT1) inhibitors

“…18 A study by Wang et al demonstrated that PRMT1 inhibitors could significantly suppress the growth of castrate-resistant prostate cancer cells. 19 Due to the potential applications of PRMT1 inhibitors in cancer therapy, discovery of PRMT1 inhibitors has recently attracted much attention. To date, a number of PRMT1 inhibitors have been reported.…”