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Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues.
Noto, Paul B; Sikorski, Timothy W; Zappacosta, Francesca; Wagner, Craig D; Montes de Oca, Rocio; Szapacs, Matthew E; Annan, Roland S; Liu, Yan; McHugh, Charles F; Mohammad, Helai P; Piccoli, Steven P; Creasy, Caretha L.
Afiliación
  • Noto PB; Experimental Medicine Unit, Oncology R&D, GSK, Collegeville, USA. paul.x.noto@gsk.com.
  • Sikorski TW; Protein Mass Spectrometry, In Vitro/In Vivo Translation, Research, GSK, Collegeville, USA.
  • Zappacosta F; Discovery Analytical, Medicinal Science and Technology, Research, GSK, Collegeville, USA.
  • Wagner CD; Discovery Analytical, Medicinal Science and Technology, Research, GSK, Collegeville, USA.
  • Montes de Oca R; Experimental Medicine Unit, Oncology R&D, GSK, Collegeville, USA.
  • Szapacs ME; Protein Mass Spectrometry, In Vitro/In Vivo Translation, Research, GSK, Collegeville, USA.
  • Annan RS; Discovery Analytical, Medicinal Science and Technology, Research, GSK, Collegeville, USA.
  • Liu Y; Epigenetics, Oncology R&D, GSK, Collegeville, USA.
  • McHugh CF; Discovery DMPK, In Vitro / In Vivo Translation, Research, GSK, Collegeville, USA.
  • Mohammad HP; Epigenetics, Oncology R&D, GSK, Collegeville, USA.
  • Piccoli SP; Experimental Medicine Unit, Oncology R&D, GSK, Collegeville, USA.
  • Creasy CL; Clinical Biomarkers and Diagnostics, Sun Pharmaceutical Advanced Research Center (SPARC), Princeton, USA.
Sci Rep ; 10(1): 22155, 2020 12 17.
Article en En | MEDLINE | ID: mdl-33335114
Arginine methylation has been recognized as a post-translational modification with pleiotropic effects that span from regulation of transcription to metabolic processes that contribute to aberrant cell proliferation and tumorigenesis. This has brought significant attention to the development of therapeutic strategies aimed at blocking the activity of protein arginine methyltransferases (PRMTs), which catalyze the formation of various methylated arginine products on a wide variety of cellular substrates. GSK3368715 is a small molecule inhibitor of type I PRMTs currently in clinical development. Here, we evaluate the effect of type I PRMT inhibition on arginine methylation in normal human peripheral blood mononuclear cells and utilize a broad proteomic approach to identify type I PRMT substrates. This work identified heterogenous nuclear ribonucleoprotein A1 (hnRNP-A1) as a pharmacodynamic biomarker of type I PRMT inhibition. Utilizing targeted mass spectrometry (MS), methods were developed to detect and quantitate changes in methylation of specific arginine residues on hnRNP-A1. This resulted in the development and validation of novel MS and immune assays useful for the assessment of GSK3368715 induced pharmacodynamic effects in blood and tumors that can be applied to GSK3368715 clinical trials.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína-Arginina N-Metiltransferasas / Proteínas Represoras / Biomarcadores / Ribonucleoproteína Nuclear Heterogénea A1 / Antineoplásicos Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Sci Rep Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína-Arginina N-Metiltransferasas / Proteínas Represoras / Biomarcadores / Ribonucleoproteína Nuclear Heterogénea A1 / Antineoplásicos Tipo de estudio: Diagnostic_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Sci Rep Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido