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Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss.
Fedoriw, Andrew; Rajapurkar, Satyajit R; O'Brien, Shane; Gerhart, Sarah V; Mitchell, Lorna H; Adams, Nicholas D; Rioux, Nathalie; Lingaraj, Trupti; Ribich, Scott A; Pappalardi, Melissa B; Shah, Niyant; Laraio, Jenny; Liu, Yan; Butticello, Michael; Carpenter, Chris L; Creasy, Caretha; Korenchuk, Susan; McCabe, Michael T; McHugh, Charles F; Nagarajan, Raman; Wagner, Craig; Zappacosta, Francesca; Annan, Roland; Concha, Nestor O; Thomas, Roberta A; Hart, Timothy K; Smith, Jesse J; Copeland, Robert A; Moyer, Mikel P; Campbell, John; Stickland, Kim; Mills, James; Jacques-O'Hagan, Suzanne; Allain, Christina; Johnston, Danielle; Raimondi, Alejandra; Porter Scott, Margaret; Waters, Nigel; Swinger, Kerren; Boriack-Sjodin, Ann; Riera, Tom; Shapiro, Gideon; Chesworth, Richard; Prinjha, Rabinder K; Kruger, Ryan G; Barbash, Olena; Mohammad, Helai P.
Afiliación
  • Fedoriw A; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Rajapurkar SR; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • O'Brien S; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Gerhart SV; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Mitchell LH; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Adams ND; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Rioux N; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Lingaraj T; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Ribich SA; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Pappalardi MB; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Shah N; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Laraio J; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Liu Y; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Butticello M; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Carpenter CL; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Creasy C; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Korenchuk S; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • McCabe MT; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • McHugh CF; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Nagarajan R; Medicinal Science and Technology, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Wagner C; Medicinal Science and Technology, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Zappacosta F; Medicinal Science and Technology, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Annan R; Medicinal Science and Technology, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Concha NO; Medicinal Science and Technology, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Thomas RA; Nonclinical Safety Assessment, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Hart TK; Nonclinical Safety Assessment, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Smith JJ; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Copeland RA; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Moyer MP; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Campbell J; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Stickland K; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Mills J; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Jacques-O'Hagan S; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Allain C; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Johnston D; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Raimondi A; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Porter Scott M; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Waters N; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Swinger K; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Boriack-Sjodin A; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Riera T; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Shapiro G; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Chesworth R; Epizyme, Inc, Cambridge, MA 02139, USA.
  • Prinjha RK; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Kruger RG; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Barbash O; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.
  • Mohammad HP; Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA. Electronic address: helai.x.mohammad@gsk.com.
Cancer Cell ; 36(1): 100-114.e25, 2019 07 08.
Article en En | MEDLINE | ID: mdl-31257072
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.
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Texto completo: 1 Colección: 01-internacional Asunto principal: Proteína-Arginina N-Metiltransferasas / Purina-Nucleósido Fosforilasa / Inhibidores Enzimáticos / Antineoplásicos Límite: Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Asunto principal: Proteína-Arginina N-Metiltransferasas / Purina-Nucleósido Fosforilasa / Inhibidores Enzimáticos / Antineoplásicos Límite: Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos