GSK3326595(cas 1616392-22-3) is a PRMT5 inhibitor. Protein Arginine Methyltransferase 5 (PRMT5) is known to symmetrically dimethylate numerous cytosolic and nuclear proteins that are involved in a variety of cellular processes.
1. Bioorg Med Chem Lett. 2019 Jun 1;29(11):1264-1269. doi:
10.1016/j.bmcl.2019.03.042. Epub 2019 Mar 27.
Nucleoside protein arginine methyltransferase 5 (PRMT5) inhibitors.
Lin H(1), Luengo JI(1).
(1)Prelude Therapeutics, 200 Powder Mill Road, Wilmington, DE 19803, United
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
2. Expert Opin Ther Pat. 2019 Feb;29(2):97-114. doi: 10.1080/13543776.2019.1567711.
A patent review of arginine methyltransferase inhibitors (2010-2018).
Li X(1)(2), Wang C(1)(2), Jiang H(1)(2), Luo C(1)(2).
(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
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
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.
3. Sci Rep. 2018 Jun 26;8(1):9711. doi: 10.1038/s41598-018-28002-y.
Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to
PRMT5 inhibition through its role in regulating cellular splicing.
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
(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@example.com.
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.