Cited by 569Cancer-related gene regulationProtein Degradation and InhibitorsPolyamine Metabolism and Applications

A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models

Chan-Penebre, Elayne, Kuplast, Kristy G, Majer, Christina R, Boriack-Sjodin, P Ann, Wigle, Tim J, Johnston, L Danielle, Rioux, Nathalie, Munchhof, Michael J +22 more·2015·Nature Chemical Biology

Abstract

Protein arginine methyltransferase-5 (PRMT5) is reported to have a role in diverse cellular processes, including tumorigenesis, and its overexpression is observed in cell lines and primary patient samples derived from lymphomas, particularly mantle cell lymphoma (MCL). Here we describe the identification and characterization of a potent and selective inhibitor of PRMT5 with antiproliferative effects in both in vitro and in vivo models of MCL. EPZ015666 (GSK3235025) is an orally available inhibitor of PRMT5 enzymatic activity in biochemical assays with a half-maximal inhibitory concentration (IC50) of 22 nM and broad selectivity against a panel of other histone methyltransferases. Treatment of MCL cell lines with EPZ015666 led to inhibition of SmD3 methylation and cell death, with IC50 values in the nanomolar range. Oral dosing with EPZ015666 demonstrated dose-dependent antitumor activity in multiple MCL xenograft models. EPZ015666 represents a validated chemical probe for further study of PRMT5 biology and arginine methylation in cancer and other diseases.

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Crossref · 10.1038/nchembio.1810

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Authors
Chan-Penebre, E., Kuplast, K. G., Majer, C. R., Boriack-Sjodin, P. A., Wigle, T. J., Johnston, L. D., Rioux, N., Munchhof, M. J., Jin, L., Jacques, S. L., West, K. A., Lingaraj, T., Stickland, K., Ribich, S. A., Raimondi, A., Scott, M. P., Waters, N. J., Pollock, R. M., Smith, J. J., Barbash, O., Pappalardi, M., Ho, T. F., Nurse, K., Oza, K. P., Gallagher, K. T., Kruger, R., Moyer, M. P., Copeland, R. A., Chesworth, R., & Duncan, K. W.
Affiliations
  • Epizyme (United States) (US)
  • Genentech (US)
  • GlaxoSmithKline (United States) (US)
Corresponding author
Duncan, Kenneth W
Venue
Nature Chemical Biology
Published
2015-04-27
Volume
11
Issue
6
Pages
432-437
ISSN
  • 1552-4450 (ISSN-L)
  • 1552-4469
OpenAlex
W2071576183
Cited by
569
References
54
Citations by year
2026: 35 · 2025: 47 · 2024: 49 · 2023: 58 · 2022: 57 · 2021: 67 · 2020: 44 · 2019: 61 · 2018: 51 · 2017: 45 · 2016: 36 · 2015: 17
FWCI
22.16
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Chemical Biology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
Keywords
PRMT5, symmetric dimethylation, arginine methylation, mantle cell lymphoma, histone methyltransferase, antiproliferative activity, xenograft models, chemical probes
MeSH terms
Animals, Antineoplastic Agents, Dose-Response Relationship, Drug, Humans, Isoquinolines, Male, Methylation, Mice, Inbred Strains, Models, Molecular, Protein-Arginine N-Methyltransferases, Protein Binding, Pyrimidines, Molecular Structure, Cell Death, Crystallography, X-Ray, Inhibitory Concentration 50, Lymphoma, Mantle-Cell, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, snRNP Core Proteins

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