A patent review of arginine methyltransferase inhibitors (2010–2018)

ABSTRACT

Introduction: Protein arginine methyltransferases (PRMTs) are fundamental enzymes that specifically modify the arginine residues of versatile substrates in cells. The aberrant expression and abnormal enzymatic activity of PRMTs are associated with many human diseases, especially cancer. PRMTs are emerging as promising drug targets in both academia and industry.

Areas covered: This review summarizes the updated patented inhibitors targeting PRMTs from 2010 to 2018. The authors illustrate the chemical structures, molecular mechanism of action, pharmacological activities as well as the potential clinical application including combination therapy and biomarker-guided therapy. PRMT inhibitors in clinical trials are also highlighted. The authors provide a future perspective for further development of potent and selective PRMT inhibitors.

Expert opinion: Although a number of small molecule inhibitors of PRMTs with sufficient potency have been developed, the selectivity of most PRMT inhibitors remains to be improved. Hence, novel approaches such as allosteric regulation need to be further studied to identify PRMT inhibitors. So far, three PRMT inhibitors have entered clinical trials, including PRMT5 inhibitor GSK3326595 and JNJ-64619178 as well as PRMT1 inhibitor GSK3368715. PRMT inhibitors with novel mechanism of action and good drug-like properties may shed new light on drug research and development progress.

KEYWORDS:

• Arginine methylation
• Protein arginine methyltransferases (PRMTs)
• small molecule inhibitors
• drug research and development

Article highlights

• This review summarizes the patented inhibitors targeting PRMTs from 2010 to 2018 and illustrates the chemical structures of PRMT inhibitors as well as their biological activities.

• The combination therapies of PRMT inhibitors and immunotherapy antibodies such as anti-PD-1 or anti-OX40 antibodies show significant efficacy in mouse model.

• So far, three PRMT inhibitors are being tested in clinical research: PRMT5 inhibitor GSK3326595, and JNJ-64619178 as well as PRMT1 inhibitor GSK3368715.

• New mechanisms of PRMT inhibition such as allosteric regulation need to be further researched for developing inhibitors with high selectivity.

This box summarizes key points contained in the article.

Declaration of interest

The authors declare that they work for the Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received financial support from the National Natural Science Foundation of China (81625022, 91853205, 81430084, 81821005). K. C. Wong Education Foundation and Chinese Academy of Sciences (XDA12020353 and XDA12050401), Science and Technology Commission of Shanghai Municipality(18431907100).