دورية أكاديمية
Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues.
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. |
References: | J Biol Chem. 2005 Sep 23;280(38):32890-6. (PMID: 16051612) Rapid Commun Mass Spectrom. 2004;18(8):877-81. (PMID: 15095356) J Am Soc Mass Spectrom. 1994 Nov;5(11):976-89. (PMID: 24226387) Mol Cell. 2009 Jan 16;33(1):1-13. (PMID: 19150423) Cell Mol Biol Lett. 2009;14(4):657-69. (PMID: 19557313) Mol Cell. 2005 Apr 29;18(3):263-72. (PMID: 15866169) J Cell Sci. 2007 Dec 15;120(Pt 24):4243-6. (PMID: 18057026) Annu Rev Biochem. 1993;62:289-321. (PMID: 8352591) Oncotarget. 2017 Jul 18;8(33):55453-55466. (PMID: 28903433) Bioinformatics. 2010 Apr 1;26(7):966-8. (PMID: 20147306) Nat Rev Cancer. 2013 Jan;13(1):37-50. (PMID: 23235912) Biochemistry. 1994 Sep 20;33(37):11382-90. (PMID: 7727389) Cell Cycle. 2014;13(1):32-41. (PMID: 24296620) J Biol Chem. 1994 Jan 14;269(2):1075-82. (PMID: 8288564) Cancer Res. 2000 Jul 1;60(13):3493-503. (PMID: 10910061) Proc Natl Acad Sci U S A. 1971 Apr;68(4):765-9. (PMID: 4994464) J Biol Chem. 1995 Jun 30;270(26):15884-91. (PMID: 7541049) Int J Mol Sci. 2013 Sep 16;14(9):18999-9024. (PMID: 24065100) Mol Cell Proteomics. 2014 Jan;13(1):372-87. (PMID: 24129315) Mol Cell Proteomics. 2012 May;11(5):187-201. (PMID: 22322096) Cancer Cell. 2019 Jul 8;36(1):100-114.e25. (PMID: 31257072) Immunity. 2005 Aug;23(2):177-89. (PMID: 16111636) Sci Rep. 2013;3:1311. (PMID: 23419748) Endocr Rev. 2005 Apr;26(2):147-70. (PMID: 15479858) J Biol Chem. 2004 May 28;279(22):22902-7. (PMID: 15044439) Exp Cell Res. 1995 Nov;221(1):187-96. (PMID: 7589244) Nucleic Acids Res. 2017 May 5;45(8):4359-4369. (PMID: 28115626) Biochemistry. 1997 Apr 29;36(17):5185-92. (PMID: 9136880) Proc Natl Acad Sci U S A. 2004 Jun 8;101(23):8551-6. (PMID: 15161980) Eukaryot Cell. 2011 Aug;10(8):1013-22. (PMID: 21685318) |
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 |
تدمد: | 2045-2322 |
---|---|
DOI: | 10.1038/s41598-020-78800-6 |