Title |
A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models
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Published in |
Nature Chemical Biology, April 2015
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DOI | 10.1038/nchembio.1810 |
Pubmed ID | |
Authors |
Elayne Chan-Penebre, Kristy G Kuplast, Christina R Majer, P Ann Boriack-Sjodin, Tim J Wigle, L Danielle Johnston, Nathalie Rioux, Michael J Munchhof, Lei Jin, Suzanne L Jacques, Kip A West, Trupti Lingaraj, Kimberly Stickland, Scott A Ribich, Alejandra Raimondi, Margaret Porter Scott, Nigel J Waters, Roy M Pollock, Jesse J Smith, Olena Barbash, Melissa Pappalardi, Thau F Ho, Kelvin Nurse, Khyati P Oza, Kathleen T Gallagher, Ryan Kruger, Mikel P Moyer, Robert A Copeland, Richard Chesworth, Kenneth W Duncan |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 2 | 29% |
Spain | 1 | 14% |
Australia | 1 | 14% |
Unknown | 3 | 43% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 6 | 86% |
Scientists | 1 | 14% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Denmark | 2 | <1% |
Japan | 2 | <1% |
Netherlands | 1 | <1% |
Germany | 1 | <1% |
United States | 1 | <1% |
Unknown | 349 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 80 | 22% |
Student > Ph. D. Student | 74 | 21% |
Student > Bachelor | 35 | 10% |
Student > Master | 34 | 10% |
Student > Doctoral Student | 13 | 4% |
Other | 48 | 13% |
Unknown | 72 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 100 | 28% |
Agricultural and Biological Sciences | 65 | 18% |
Chemistry | 53 | 15% |
Medicine and Dentistry | 25 | 7% |
Pharmacology, Toxicology and Pharmaceutical Science | 16 | 4% |
Other | 16 | 4% |
Unknown | 81 | 23% |