A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models
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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Preclinical modelling of resistance mechanisms has shown that resistance to epigenetic therapies largely emerges through cellular reprogramming and transcriptional plasticity.
“Preclinical modelling of resistance mechanisms has shown that resistance to these therapies largely emerge through cellular reprogramming and transcriptional plasticity 184-186 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [184]
Epigenetic therapies targeting MYC through transcriptional repression are only transiently effective as cancer cells evolve multiple adaptive responses to retain MYC expression.
“whilst several epigenetic therapies targeting the prototypical oncogene MYC through transcriptional repression generated much excitement, it is now clear that this is only transiently effective as cancer cells evolve multiple adaptive responses to retain MYC expression 184-186 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [184]
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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
- ORCID
- 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
- Licence
- www.springer.com/tdm (tdm)
- 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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