دورية أكاديمية
أعرض في EDS

Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues.

التفاصيل البيبلوغرافية
العنوان: Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues.
المؤلفون: 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.; Clinical Biomarkers and Diagnostics, Sun Pharmaceutical Advanced Research Center (SPARC), Princeton, USA., Creasy CL; Epigenetics, Oncology R&D, GSK, Collegeville, USA.
المصدر: Scientific reports [Sci Rep] 2020 Dec 17; Vol. 10 (1), pp. 22155. Date of Electronic Publication: 2020 Dec 17.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Biomarkers*, Antineoplastic Agents/*pharmacokinetics , Heterogeneous Nuclear Ribonucleoprotein A1/*metabolism , Protein-Arginine N-Methyltransferases/*antagonists & inhibitors , Repressor Proteins/*antagonists & inhibitors, Animals ; Antineoplastic Agents/therapeutic use ; Antineoplastic Agents, Immunological/chemistry ; Antineoplastic Agents, Immunological/pharmacokinetics ; Antineoplastic Agents, Immunological/pharmacology ; Arginine/metabolism ; Cells, Cultured ; Chromatography, Liquid ; Drug Monitoring ; Enzyme Activation ; Enzyme Inhibitors/pharmacokinetics ; Enzyme Inhibitors/therapeutic use ; Gene Expression Regulation, Neoplastic/drug effects ; Heterogeneous Nuclear Ribonucleoprotein A1/blood ; Humans ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/metabolism ; Mass Spectrometry ; Methylation ; Mice ; Molecular Targeted Therapy ; Neoplasms/blood ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Protein-Arginine N-Methyltransferases/genetics ; Repressor Proteins/genetics ; Substrate Specificity
مستخلص: 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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المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Antineoplastic Agents, Immunological)
0 (Biomarkers)
0 (Enzyme Inhibitors)
0 (Heterogeneous Nuclear Ribonucleoprotein A1)
0 (Repressor Proteins)
0 (hnRNPA1 protein, human)
94ZLA3W45F (Arginine)
EC 2.1.1.319 (PRMT1 protein, human)
EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
تواريخ الأحداث: Date Created: 20201218 Date Completed: 20210510 Latest Revision: 20210510
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC7746746
DOI: 10.1038/s41598-020-78800-6
PMID: 33335114
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-020-78800-6