دورية أكاديمية
أعرض في EDS

Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma.

التفاصيل البيبلوغرافية
العنوان: Identification of a CARM1 Inhibitor with Potent In Vitro and In Vivo Activity in Preclinical Models of Multiple Myeloma.
المؤلفون: Drew AE; Epizyme, Inc., Cambridge, Massachusetts, USA. adrew@epizyme.com., Moradei O; Epizyme, Inc., Cambridge, Massachusetts, USA., Jacques SL; Epizyme, Inc., Cambridge, Massachusetts, USA., Rioux N; Epizyme, Inc., Cambridge, Massachusetts, USA., Boriack-Sjodin AP; Epizyme, Inc., Cambridge, Massachusetts, USA., Allain C; Epizyme, Inc., Cambridge, Massachusetts, USA., Scott MP; Epizyme, Inc., Cambridge, Massachusetts, USA., Jin L; Epizyme, Inc., Cambridge, Massachusetts, USA., Raimondi A; Epizyme, Inc., Cambridge, Massachusetts, USA., Handler JL; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania, USA., Ott HM; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania, USA., Kruger RG; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania, USA., McCabe MT; Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania, USA., Sneeringer C; Epizyme, Inc., Cambridge, Massachusetts, USA., Riera T; Epizyme, Inc., Cambridge, Massachusetts, USA., Shapiro G; Epizyme, Inc., Cambridge, Massachusetts, USA., Waters NJ; Epizyme, Inc., Cambridge, Massachusetts, USA., Mitchell LH; Epizyme, Inc., Cambridge, Massachusetts, USA., Duncan KW; Epizyme, Inc., Cambridge, Massachusetts, USA., Moyer MP; Epizyme, Inc., Cambridge, Massachusetts, USA., Copeland RA; Epizyme, Inc., Cambridge, Massachusetts, USA., Smith J; Epizyme, Inc., Cambridge, Massachusetts, USA., Chesworth R; Epizyme, Inc., Cambridge, Massachusetts, USA., Ribich SA; Epizyme, Inc., Cambridge, Massachusetts, USA.
المصدر: Scientific reports [Sci Rep] 2017 Dec 21; Vol. 7 (1), pp. 17993. Date of Electronic Publication: 2017 Dec 21.
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
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Antineoplastic Agents/*therapeutic use , CARD Signaling Adaptor Proteins/*antagonists & inhibitors , Enzyme Inhibitors/*therapeutic use , Guanylate Cyclase/*antagonists & inhibitors , Isoxazoles/*therapeutic use , Multiple Myeloma/*drug therapy , Pyrimidines/*therapeutic use , Spiro Compounds/*therapeutic use, Animals ; Antineoplastic Agents/pharmacokinetics ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/pharmacokinetics ; Humans ; In Vitro Techniques ; Isoxazoles/pharmacokinetics ; Male ; Mice ; Neoplasm Transplantation ; Pyrimidines/pharmacokinetics ; Rats, Sprague-Dawley ; Spiro Compounds/pharmacokinetics
مستخلص: CARM1 is an arginine methyltransferase with diverse histone and non-histone substrates implicated in the regulation of cellular processes including transcriptional co-activation and RNA processing. CARM1 overexpression has been reported in multiple cancer types and has been shown to modulate oncogenic pathways in in vitro studies. Detailed understanding of the mechanism of action of CARM1 in oncogenesis has been limited by a lack of selective tool compounds, particularly for in vivo studies. We describe the identification and characterization of, to our knowledge, the first potent and selective inhibitor of CARM1 that exhibits anti-proliferative effects both in vitro and in vivo and, to our knowledge, the first demonstration of a role for CARM1 in multiple myeloma (MM). EZM2302 (GSK3359088) is an inhibitor of CARM1 enzymatic activity in biochemical assays (IC 50  = 6 nM) with broad selectivity against other histone methyltransferases. Treatment of MM cell lines with EZM2302 leads to inhibition of PABP1 and SMB methylation and cell stasis with IC 50 values in the nanomolar range. Oral dosing of EZM2302 demonstrates dose-dependent in vivo CARM1 inhibition and anti-tumor activity in an MM xenograft model. EZM2302 is a validated chemical probe suitable for further understanding the biological role CARM1 plays in cancer and other diseases.
References: Oncol Rep. 2013 Oct;30(4):1669-74. (PMID: 23912631)
J Biol Chem. 2000 Sep 15;275(37):28826-33. (PMID: 10889208)
Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3100-5. (PMID: 16492776)
Diagn Pathol. 2013 Aug 02;8:129. (PMID: 23915145)
Onco Targets Ther. 2017 Feb 20;10 :1027-1038. (PMID: 28255246)
Cancer Cell. 2014 Jan 13;25(1):21-36. (PMID: 24434208)
J Med Chem. 2016 Jul 28;59(14 ):6838-47. (PMID: 27390919)
Bioorg Med Chem Lett. 2008 Aug 1;18(15):4438-41. (PMID: 18619839)
Biochem J. 2011 Jun 1;436(2):331-9. (PMID: 21410432)
J Biol Chem. 2002 Jul 19;277(29):26031-5. (PMID: 11983685)
Cell Rep. 2013 Dec 26;5(6):1625-38. (PMID: 24332853)
Proc Natl Acad Sci U S A. 2013 May 7;110(19):7922-7. (PMID: 23620515)
Bioorg Med Chem Lett. 2009 Sep 1;19(17 ):5063-6. (PMID: 19632837)
BMC Mol Biol. 2013 Jul 09;14 :15. (PMID: 23837869)
EMBO Rep. 2002 Mar;3(3):268-73. (PMID: 11850402)
Mol Cancer Res. 2011 May;9(5):660-70. (PMID: 21478268)
Mol Cancer Ther. 2014 Apr;13(4):842-54. (PMID: 24563539)
Bioorg Med Chem Lett. 2009 Feb 15;19(4):1218-23. (PMID: 19131248)
Methods Biochem Anal. 2005;46:1-265. (PMID: 16350889)
Bioorg Med Chem Lett. 2009 Jun 1;19(11):2924-7. (PMID: 19419866)
Nature. 2012 Dec 6;492(7427):108-12. (PMID: 23051747)
Mol Cell Biol. 2004 Mar;24(5):2103-17. (PMID: 14966289)
Cell Mol Life Sci. 2009 Jul;66(13):2109-21. (PMID: 19300908)
J Med Chem. 2016 Oct 13;59(19):9124-9139. (PMID: 27584694)
Cancer Cell. 2011 Jul 12;20(1):53-65. (PMID: 21741596)
Cancer Res. 2008 Jan 1;68(1):301-6. (PMID: 18172323)
Chem Biol Drug Des. 2010 Jun;75(6):535-40. (PMID: 20374252)
Biochemistry. 2001 May 15;40(19):5747-56. (PMID: 11341840)
Biochemistry. 2016 Mar 22;55(11):1635-44. (PMID: 26848779)
ACS Med Chem Lett. 2015 Apr 06;6(6):655-9. (PMID: 26101569)
Mol Cell Biol. 2007 Jan;27(1):120-34. (PMID: 17043108)
Mol Cell. 2007 Jan 12;25(1):71-83. (PMID: 17218272)
Nat Chem Biol. 2015 Jun;11(6):432-7. (PMID: 25915199)
PLoS One. 2012;7(6):e34692. (PMID: 22723830)
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6464-8. (PMID: 12756295)
Cancer. 2004 Jul 1;101(1):83-9. (PMID: 15221992)
Prostate. 2006 Sep 1;66(12 ):1292-301. (PMID: 16705743)
Bioorg Med Chem Lett. 2009 Dec 1;19(23 ):6725-32. (PMID: 19836951)
EMBO Rep. 2008 Feb;9(2):193-8. (PMID: 18188184)
J Med Chem. 2011 Jul 14;54(13):4928-32. (PMID: 21612300)
Nat Cell Biol. 2017 Nov;19(11):1358-1370. (PMID: 29058718)
Nat Commun. 2017 May 24;8:15571. (PMID: 28537268)
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (CARD Signaling Adaptor Proteins)
0 (Enzyme Inhibitors)
0 (Isoxazoles)
0 (Pyrimidines)
0 (Spiro Compounds)
EC 4.6.1.2 (CARD11 protein, human)
EC 4.6.1.2 (Guanylate Cyclase)
تواريخ الأحداث: Date Created: 20171223 Date Completed: 20190730 Latest Revision: 20190730
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC5740082
DOI: 10.1038/s41598-017-18446-z
PMID: 29269946
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-017-18446-z