title: A novel small-molecule inhibitor of mcl-1 blocks pancreatic cancer growth in vitro and in vivo.
abstract: Using a high-throughput screening (HTS) approach, we have identified and validated several small-molecule Mcl-1 inhibitors (SMI). Here, we describe a novel selective Mcl-1 SMI inhibitor, 2 (UMI-77), developed by structure-based chemical modifications of the lead compound 1 (UMI-59). We have characterized the binding of UMI-77 to Mcl-1 by using complementary biochemical, biophysical, and computational methods and determined its antitumor activity against a panel of pancreatic cancer cells and an in vivo xenograft model. UMI-77 binds to the BH3-binding groove of Mcl-1 with Ki of 490 nmol/L, showing selectivity over other members of the antiapoptotic Bcl-2 family. UMI-77 inhibits cell growth and induces apoptosis in pancreatic cancer cells in a time- and dose-dependent manner, accompanied by cytochrome c release and caspase-3 activation. Coimmunoprecipitation experiments revealed that UMI-77 blocks the heterodimerization of Mcl-1/Bax and Mcl-1/Bak in cells, thus antagonizing the Mcl-1 function. The Bax/Bak-dependent induction of apoptosis was further confirmed using murine embryonic fibroblasts that are Bax- and Bak-deficient. In an in vivo BxPC-3 xenograft model, UMI-77 effectively inhibited tumor growth. Western blot analysis in tumor remnants revealed enhancement of proapoptotic markers and significant decrease of survivin. Collectively, these promising findings show the therapeutic potential of Mcl-1 inhibitors against pancreatic cancer and warrant further preclinical investigations.
authors.affiliation: Corresponding Author: Zaneta Nikolovska-Coleska, 4510E MSRB I, 1150 West Medical Center Drive, Ann Arbor, MI 48109. zanetan@med.umich.edu.
authors.forename: Fardokht
authors.initials: F
authors.lastname: Abulwerdi
authors.forename: Chenzhong
authors.initials: C
authors.lastname: Liao
authors.forename: Meilan
authors.initials: M
authors.lastname: Liu
authors.forename: Asfar S
authors.initials: AS
authors.lastname: Azmi
authors.forename: Amro
authors.initials: A
authors.lastname: Aboukameel
authors.forename: Ahmed S A
authors.initials: AS
authors.lastname: Mady
authors.forename: Thippeswamy
authors.initials: T
authors.lastname: Gulappa
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.forename: Scott
authors.initials: S
authors.lastname: Owens
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
authors.forename: Ramzi M
authors.initials: RM
authors.lastname: Mohammad
authors.forename: Zaneta
authors.initials: Z
authors.lastname: Nikolovska-Coleska
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019281:Dimerization; D006801:Humans; D007854:Lead / Q000008:administration & dosage*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage*; D013864:Thioglycolates / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000235:genetics
chemical_list: C494772:BAK1 protein, human; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D013449:Sulfonamides; D013864:Thioglycolates; C000592878:UMI-77; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D007854:Lead
references.citation: Genes Dev. 2005 Jun 1;19(11):1294-305
references.pmid: 15901672
references.citation: Cancer Res. 2008 Apr 15;68(8):2944-51
references.pmid: 18413764
references.citation: Oncogene. 2007 Feb 26;26(9):1324-37
references.pmid: 17322918
references.citation: Biochem Biophys Res Commun. 2009 Aug 14;386(1):35-9
references.pmid: 19523441
references.citation: Cancer Chemother Pharmacol. 2008 Nov;62(6):1055-64
references.pmid: 18297287
references.citation: Cancer Res. 2009 Jul 1;69(13):5575-83
references.pmid: 19549912
references.citation: Cell Death Differ. 2000 Dec;7(12):1166-73
references.pmid: 11175253
references.citation: J Biol Chem. 2005 Feb 11;280(6):4738-44
references.pmid: 15550399
references.citation: Surgery. 2010 Apr;147(4):553-61
references.pmid: 20004446
references.citation: Mol Cancer. 2008 Jul 24;7:64
references.pmid: 18652674
references.citation: Blood. 1997 Jan 15;89(2):630-43
references.pmid: 9002967
references.citation: ACS Med Chem Lett. 2012 Feb 29;3(4):308-12
references.pmid: 24900469
references.citation: Mol Cell. 2005 Feb 4;17(3):393-403
references.pmid: 15694340
references.citation: Oncology. 1999;56(1):73-82
references.pmid: 9885381
references.citation: Nature. 2005 Jun 2;435(7042):677-81
references.pmid: 15902208
references.citation: Cancer Res. 2007 Jan 15;67(2):782-91
references.pmid: 17234790
references.citation: Science. 2001 Apr 27;292(5517):727-30
references.pmid: 11326099
references.citation: Int J Cancer. 2004 Mar 20;109(2):182-8
references.pmid: 14750167
references.citation: Cancer Cell. 2006 Nov;10(5):389-99
references.pmid: 17097561
references.citation: Nat Rev Cancer. 2002 Dec;2(12):897-909
references.pmid: 12459728
references.citation: J Cell Biol. 1999 Mar 8;144(5):903-14
references.pmid: 10085290
references.citation: Mol Cell Biol. 2005 Nov;25(21):9369-82
references.pmid: 16227588
references.citation: Mol Med. 2011;17(11-12):1262-74
references.pmid: 21863213
references.citation: Science. 2007 Feb 9;315(5813):856-9
references.pmid: 17289999
references.citation: J Biol Chem. 2012 Mar 23;287(13):10224-10235
references.pmid: 22311987
references.citation: J Med Chem. 2012 May 24;55(10):4664-82
references.pmid: 22448988
references.citation: Cancer Res. 2008 May 1;68(9):3421-8
references.pmid: 18451170
references.citation: Anal Biochem. 2012 Feb 15;421(2):742-9
references.pmid: 22197419
references.citation: Expert Opin Ther Pat. 2012 Jan;22(1):37-55
references.pmid: 22195752
references.citation: Oncology. 2002;62(4):354-62
references.pmid: 12138244
references.citation: J Mol Biol. 2008 Jul 25;380(5):958-71
references.pmid: 18589438
references.citation: Oncogene. 2008 Dec;27 Suppl 1:S71-83
references.pmid: 19641508
references.citation: Curr Opin Struct Biol. 2005 Dec;15(6):690-9
references.pmid: 16263267
references.citation: J Cell Biol. 2008 Jan 28;180(2):341-55
references.pmid: 18209102
references.citation: Cell Death Differ. 2005 Aug;12 Suppl 1:942-61
references.pmid: 15665817
references.citation: J Med Chem. 2013 Jan 10;56(1):15-30
references.pmid: 23244564
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Science. 2003 Nov 7;302(5647):1036-8
references.pmid: 14500851
references.citation: Anal Biochem. 2004 Sep 15;332(2):261-73
references.pmid: 15325294
references.citation: Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6217-22
references.pmid: 17389404