| Literature DB >> 31257072 |
Andrew Fedoriw1, Satyajit R Rajapurkar1, Shane O'Brien1, Sarah V Gerhart1, Lorna H Mitchell2, Nicholas D Adams1, Nathalie Rioux2, Trupti Lingaraj2, Scott A Ribich2, Melissa B Pappalardi1, Niyant Shah1, Jenny Laraio1, Yan Liu1, Michael Butticello1, Chris L Carpenter1, Caretha Creasy1, Susan Korenchuk1, Michael T McCabe1, Charles F McHugh1, Raman Nagarajan3, Craig Wagner3, Francesca Zappacosta3, Roland Annan3, Nestor O Concha3, Roberta A Thomas4, Timothy K Hart4, Jesse J Smith2, Robert A Copeland2, Mikel P Moyer2, John Campbell2, Kim Stickland2, James Mills2, Suzanne Jacques-O'Hagan2, Christina Allain2, Danielle Johnston2, Alejandra Raimondi2, Margaret Porter Scott2, Nigel Waters2, Kerren Swinger2, Ann Boriack-Sjodin2, Tom Riera2, Gideon Shapiro2, Richard Chesworth2, Rabinder K Prinjha1, Ryan G Kruger1, Olena Barbash1, Helai P Mohammad5.
Abstract
Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.Entities:
Keywords: MTAP; PRMT5; Type I PRMT; arginine methylation; biomarker; cancer biology; post translational modifications; splicing
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Year: 2019 PMID： 31257072 DOI： 10.1016/j.ccell.2019.05.014
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743