| Reference | 1. Bioorg Med Chem Lett. 2019 Jun 1;29(11):1264-1269. doi: 10.1016/j.bmcl.2019.03.042. Epub 2019 Mar 27.<br />
Nucleoside protein arginine methyltransferase 5 (PRMT5) inhibitors.<br />
Lin H(1), Luengo JI(1).<br />
Author information:<br />
(1)Prelude Therapeutics, 200 Powder Mill Road, Wilmington, DE 19803, United States.<br />
Protein Arginine Methyltransferase 5 (PRMT5) is known to symmetrically dimethylate numerous cytosolic and nuclear proteins that are involved in a variety of cellular processes. Recent findings have revealed its potential as a cancer therapeutic target. PRMT5 selective inhibitors, GSK3326595, a substrate competitive inhibitor, and JNJ64619178, a SAM (S-adenosyl-l-methionine) mimetic/competitive inhibitor, have entered clinic trials for multiple cancer types. This review focuses on the recent developments in SAM mimetic nucleoside PRMT5 inhibitors, their SAR and structural insight based on published co-crystal structures.<br />
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2. Expert Opin Ther Pat. 2019 Feb;29(2):97-114. doi: 10.1080/13543776.2019.1567711.<br />
A patent review of arginine methyltransferase inhibitors (2010-2018).<br />
Li X(1)(2), Wang C(1)(2), Jiang H(1)(2), Luo C(1)(2).<br />
Author information:<br />
(1)a CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Drug Discovery and Design Center , Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China. (2)b Department of Pharmacy , University of Chinese Academy of Sciences , Beijing , China.<br />
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.<br />
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.<br />
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.<br />
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3. Sci Rep. 2018 Jun 26;8(1):9711. doi: 10.1038/s41598-018-28002-y.<br />
Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing.<br />
Gerhart SV(1), Kellner WA(1), Thompson C(1), Pappalardi MB(1), Zhang XP(1), Montes de Oca R(1), Penebre E(2), Duncan K(2), Boriack-Sjodin A(2), Le B(1), Majer C(2), McCabe MT(1), Carpenter C(1)(3), Johnson N(1), Kruger RG(1), Barbash O(4).<br />
Author information:<br />
(1)Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA. (2)Epizyme, Inc., Cambridge, MA, USA. (3)Rubius Therapeutics, Boston, MA, USA. (4)Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, PA, USA. [email protected].<br />
Evasion of the potent tumour suppressor activity of p53 is one of the hurdles that must be overcome for cancer cells to escape normal regulation of cellular proliferation and survival. In addition to frequent loss of function mutations, p53 wild-type activity can also be suppressed post-translationally through several mechanisms, including the activity of PRMT5. Here we describe broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase 5 (PRMT5) including GSK3326595 in human cancer cell lines representing both hematologic and solid malignancies. Interestingly, PRMT5 inhibition activates the p53 pathway via the induction of alternative splicing of MDM4. The MDM4 isoform switch and subsequent p53 activation are critical determinants of the response to PRMT5 inhibition suggesting that the integrity of the p53-MDM4 regulatory axis defines a subset of patients that could benefit from treatment with GSK3326595.<br />
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