1. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models.
- Author
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Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ, Johnston LD, Rioux N, Munchhof MJ, Jin L, Jacques SL, West KA, Lingaraj T, Stickland K, Ribich SA, Raimondi A, Scott MP, Waters NJ, Pollock RM, Smith JJ, Barbash O, Pappalardi M, Ho TF, Nurse K, Oza KP, Gallagher KT, Kruger R, Moyer MP, Copeland RA, Chesworth R, and Duncan KW
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Cell Death drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Crystallography, X-Ray, Dose-Response Relationship, Drug, Humans, Inhibitory Concentration 50, Isoquinolines chemistry, Isoquinolines therapeutic use, Lymphoma, Mantle-Cell drug therapy, Lymphoma, Mantle-Cell enzymology, Male, Methylation, Mice, Inbred Strains, Models, Molecular, Molecular Structure, Protein Binding, Pyrimidines chemistry, Pyrimidines therapeutic use, Xenograft Model Antitumor Assays, snRNP Core Proteins metabolism, Antineoplastic Agents pharmacology, Isoquinolines pharmacology, Lymphoma, Mantle-Cell pathology, Protein-Arginine N-Methyltransferases antagonists & inhibitors, Pyrimidines pharmacology
- 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.
- Published
- 2015
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