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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Review Article

Research Progress on Small-molecule Inhibitors of Protein Arginine Methyltransferase 5 (PRMT5) for Treating Cancer

Author(s): Chaohua Guo, Lintao Wu, Xumei Zheng, Lin Zhao, Xiaojia Hou, Zhijun Wang* and Chun Han*

Volume 23, Issue 21, 2023

Published on: 19 July, 2023

Page: [2048 - 2074] Pages: 27

DOI: 10.2174/1568026623666230712120527

Price: $65


Background: The protein arginine methyltransferase family includes nine members, with PRMT5 being the major type II arginine methyltransferase. PRMT5 is upregulated in a variety of tumors and promotes tumorigenesis and tumor cell proliferation and metastasis, making it a potential tumor therapy target. Recently, PRMT5 inhibitor research and development have become hotspots in the tumor therapy field.

Methods: We classified and summarized PRMT5 inhibitors according to different binding mechanisms. We mainly analyzed the structure, biological activity, and binding interactions of PRMT5 inhibitors with the PRMT5 enzyme.

Results: At present, many PRMT5 inhibitors with various mechanisms of action have been reported, including substrate-competitive inhibitors, SAM-competitive inhibitors, dual substrate-/SAMcompetitive inhibitors, allosteric inhibitors, PRMT5 degraders, MTA-cooperative PRMT5 inhibitors and PPI inhibitors.

Conclusion: These inhibitors are beneficial to the treatment of tumors. Some drugs are being used in clinical trials. PRMT5 inhibitors have broad application prospects in tumor therapy.

Keywords: PRMT5, Antitumor targets, Small-molecule inhibitors, Arginine methylation, PRMT5 enzyme activity, Drug research.

Graphical Abstract
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Briggs, K.J.; Cottrell, K.M.; Tonini, M.R.; Wilker, E.W.; Gu, L.; Davis, C.B.; Zhang, M.J.; Whittington, D.; Gotur, D.; Goldstein, M.J.; DiBenedetto, H.; Rudoltz, M.S.; Huang, A. Abstract 3941: TNG908 is an MTAPnull-selective PRMT5 inhibitor that drives tumor regressions in MTAP-deleted xenograft models across multiple histologies. Cancer Res., 2022, 82(12_Supplement), 3941.
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Siu, L.L.; Rasco, D.W.; Vinay, S.P.; Romano, P.M.; Menis, J.; Opdam, F.L.; Heinhuis, K.M.; Egger, J.L.; Gorman, S.A.; Parasrampuria, R.; Wang, K.; Kremer, B.E. METEOR-1: A phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours. Ann. Oncol., 2019, 30(SUPPLEMENT 5), v159.
Postel-Vinay, S.; Italiano, A.; Martin Romano, P.; Cassier, P.A.; Siu, L.L.; Lossos, I.S.; Hilton, J.F.; McKean, M.A.; Strauss, J.; Falchook, G.S.; De Jonge, M.J.A.; Opdam, F.L.; Rasco, D.; Vermaat, J.S.; Crossman, T.; Zajac, M.; Hainline, A.; Kremer, B.; Barbash, O. A phase I study of the safety and efficacy of the protein arginine methyltransferase 5 (PRMT5) inhibitor GSK3326595 in advanced solid tumors. Ann. Oncol., 2022, 33, S746-S747.
Kim, H.; Kim, H.; Feng, Y.; Li, Y.; Tamiya, H.; Tocci, S.; Ronai, Z.A. PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity. Sci. Transl. Med., 2020, 12(551), eaaz5683.
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