title: A chimeric SERM-histone deacetylase inhibitor approach to breast cancer therapy.
abstract: Breast cancer remains a significant cause of death in women, and few therapeutic options exist for estrogen receptor negative (ER (-)) cancers. Epigenetic reactivation of target genes using histone deacetylase (HDAC) inhibitors has been proposed in ER (-) cancers to resensitize to therapy using selective estrogen receptor modulators (SERMs) that are effective in ER (+) cancer treatment. Based upon preliminary studies in ER (+) and ER (-) breast cancer cells treated with combinations of HDAC inhibitors and SERMs, hybrid drugs, termed SERMostats, were designed with computational guidance. Assay for inhibition of four type I HDAC isoforms and antagonism of estrogenic activity in two cell lines yielded a SERMostat with 1-3 μM potency across all targets. The superior hybrid caused significant cell death in ER (-) human breast cancer cells and elicited cell death at the same concentration as the parent SERM in combination treatment and at an earlier time point.
authors: Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, UIC, 833 S. Wood St., Chicago, IL 60612-7231 (USA).
authors: Hitisha K
authors: HK
authors: Patel
authors: Marton I
authors: MI
authors: Siklos
authors: Hazem
authors: H
authors: Abdelkarim
authors: Emma L
authors: EL
authors: Mendonca
authors: Aditya
authors: A
authors: Vaidya
authors: Pavel A
authors: PA
authors: Petukhov
authors: Gregory R J
authors: GR
authors: Thatcher
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D061986:MCF-7 Cells; D015394:Molecular Structure; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D020845:Selective Estrogen Receptor Modulators; D006655:Histone Deacetylases
keywords: HDAC inhibitors; SERMs; breast cancer; estrogen receptors; histone deacetylases
references: J Med Chem. 2010 Feb 11;53(3):1347-56
references: 20055418
references: J Comput Chem. 2004 Oct;25(13):1605-12
references: 15264254
references: Cancer Lett. 2009 May 8;277(1):8-21
references: 18824292
references: Int J Cancer. 2003 Nov 10;107(3):353-8
references: 14506733
references: ACS Chem Biol. 2009 Dec 18;4(12):1039-49
references: 19839584
references: Endocr Relat Cancer. 2007 Dec;14(4):1021-8
references: 18045953
references: Chem Biol. 2012 Aug 24;19(8):963-71
references: 22921063
references: J Med Chem. 2007 May 31;50(11):2682-92
references: 17489582
references: Oncogene. 2005 Jul 21;24(31):4894-907
references: 15870696
references: J Cancer Res Clin Oncol. 2008 Aug;134(8):883-90
references: 18264725
references: J Biol Chem. 2001 Oct 5;276(40):36869-72
references: 11459850
references: J Med Chem. 2010 Dec 23;53(24):8546-55
references: 21080629
references: ChemMedChem. 2007 Oct;2(10):1520-6
references: 17654759
references: Breast Cancer Res Treat. 2003 Oct;81(3):177-86
references: 14620913
references: Cancer Res. 2006 Jun 15;66(12):6370-8
references: 16778215
references: Endocr Rev. 2013 Feb;34(1):1-32
references: 22947396
references: Br J Cancer. 2011 Jun 7;104(12):1828-35
references: 21559012
references: Biochem Pharmacol. 2008 May 1;75(9):1697-705
references: 18342836
references: Cancer Res. 2001 Oct 1;61(19):7025-9
references: 11585728
references: Bioorg Med Chem Lett. 2008 Jan 15;18(2):726-31
references: 18060775
references: Clin Cancer Res. 2007 Aug 15;13(16):4882-90
references: 17699868
references: Eur J Cancer. 2008 Dec;44(18):2799-805
references: 19008097
references: Breast Cancer Res Treat. 2007 Nov;105(3):297-309
references: 17186358
references: J Med Chem. 2011 Jul 14;54(13):4350-64
references: 21548582
references: Oncogene. 2004 Mar 4;23(9):1724-36
references: 14676837
references: Int J Breast Cancer. 2012;2012:654698
references: 22295247
references: Cancer Lett. 2009 Aug 8;280(2):184-91
references: 19185986
references: Cancer Biol Ther. 2007 Jan;6(1):64-9
references: 17172825
references: Bioorg Med Chem Lett. 2012 Aug 1;22(15):5025-30
references: 22771007
references: Nature. 1997 Oct 16;389(6652):753-8
references: 9338790
references: Mol Cell Biochem. 2012 Jul;366(1-2):111-22
references: 22476901
references: Breast Cancer Res Treat. 2008 May;109(2):241-50
references: 17638070
references: Chem Pharm Bull (Tokyo). 2009 Sep;57(9):897-906
references: 19721249
references: Cancer Res. 2004 Feb 15;64(4):1522-33
references: 14973112
references: J Med Chem. 1997 May 9;40(10):1407-16
references: 9154963
references: Cancer Res. 2006 Jul 15;66(14):7334-40
references: 16849584
references: Expert Opin Ther Pat. 2013 Oct;23(10):1247-71
references: 23713677
references: Bioorg Med Chem. 2008 May 1;16(9):4839-53
references: 18397827
references: J Cell Physiol. 2012 Oct;227(10):3426-33
references: 22213035
references: Cancer Res. 2008 Mar 1;68(5):1513-9
references: 18316616
references: Cancer Res. 2000 Dec 15;60(24):6890-4
references: 11156387
references: J Med Chem. 2010 Jan 28;53(2):616-23
references: 19961183
references: Bioconjug Chem. 2012 Nov 21;23(11):2139-58
references: 23036054
references: Breast Cancer Res Treat. 2011 Nov;130(2):437-47
references: 21298336
references: Oncogene. 2003 Oct 20;22(47):7316-39
references: 14576841
references: Clin Cancer Res. 1996 May;2(5):805-10
references: 9816234
references: J Mol Endocrinol. 2004 Apr;32(2):583-94
references: 15072561
references: Science. 2002 Mar 29;295(5564):2465-8
references: 11923541
references: J Med Chem. 2008 Nov 27;51(22):7021-40
references: 18975926
references: ACS Chem Neurosci. 2011 May 18;2(5):256-268
references: 21731800
references: Bioorg Med Chem Lett. 2010 May 15;20(10):3142-5
references: 20392638
references: Mol Endocrinol. 2005 Jul;19(7):1740-51
references: 15746193
references: Br J Cancer. 2009 Oct 6;101(7):1044-50
references: 19738609