Small Molecule Inhibitors of Protein Arginine Methyltransferases

ABSTRACT

Introduction: Arginine methylation is an abundant posttranslational modification occurring in mammalian cells and catalyzed by protein arginine methyltransferases (PRMTs). Misregulation and aberrant expression of PRMTs are associated with various disease states, notably cancer. PRMTs are prominent therapeutic targets in drug discovery.

Areas covered: The authors provide an updated review of the research on the development of chemical modulators for PRMTs. Great efforts are seen in screening and designing potent and selective PRMT inhibitors, and a number of micromolar and submicromolar inhibitors have been obtained for key PRMT enzymes such as PRMT1, CARM1, and PRMT5. The authors provide a focus on their chemical structures, mechanism of action, and pharmacological activities. Pros and cons of each type of inhibitors are also discussed.

Expert opinion: Several key challenging issues exist in PRMT inhibitor discovery. Structural mechanisms of many PRMT inhibitors remain unclear. There lacks consistency in potency data due to divergence of assay methods and conditions. Physiologically relevant cellular assays are warranted. Substantial engagements are needed to investigate pharmacodynamics and pharmacokinetics of the new PRMT inhibitors in pertinent disease models. Discovery and evaluation of potent, isoform-selective, cell-permeable and in vivo-active PRMT modulators will continue to be an active arena of research in years ahead.

KEYWORDS:

• Arginine methylation
• PRMT
• Histone methylation
• Inhibitor
• Drug discovery
• Chemical probe
• Epigenetics

Financial and Competing Interests Disclosure

The authors are supported by the National Institutes of Health through a National Institute of General Medical Sciences grant R01GM086717. The authors are also financially supported by the National Science Foundation and American Heart Association. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Article highlights

• PRMTs are crucial players in the regulation of fundamental cellular processes and disease pathways.

• PRMTs are emerging disease targets for drug discovery.

• PRMT modulators are powerful tools to elucidate PRMT function in physiology and pathology, and are potential therapeutic agents for the treatment of various diseases, notably cancer.

• Specific inhibitors have been developed for PRMT1, -3, -4, -5, and -6.

• Caution should be taken on possible off-target effects of new PRMT inhibitors.

• Breakthroughs are needed to translate PRMT inhibitors into clinical candidates.

This box summarizes key points contained in the article.