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

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  • معلومة اضافية
    • المصدر:
      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
    • بيانات النشر:
      Original Publication: London : Nature Publishing Group, copyright 2011-
    • الموضوع:
      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
    • نبذة مختصرة :
      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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    • الرقم المعرف:
      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)
    • الموضوع:
      Date Created: 20201218 Date Completed: 20210510 Latest Revision: 20210510
    • الموضوع:
      20221213
    • الرقم المعرف:
      PMC7746746
    • الرقم المعرف:
      10.1038/s41598-020-78800-6
    • الرقم المعرف:
      33335114