title: Discovery of potent and selective histone deacetylase inhibitors via focused combinatorial libraries of cyclic alpha3beta-tetrapeptides.
abstract: Histone deacetylase (HDAC) inhibitors are powerful tools in understanding epigenetic regulation and have proven especially promising for the treatment of various cancers, but the discovery of potent, isoform-selective HDAC inhibitors has been a major challenge. We recently developed a cyclic alpha(3)beta-tetrapeptide scaffold for the preparation of HDAC inhibitors with novel selectivity profiles ( J. Am. Chem. Soc. 2009 , 131 , 3033 ). In this study, we elaborate this scaffold with respect to side chain diversity by synthesizing one-bead-one-compound combinatorial libraries of cyclic tetrapeptide analogues and applying two generations of these focused libraries to the discovery of potent HDAC ligands using a convenient screening platform. Our studies led to the first HDAC6-selective cyclic tetrapeptide analogue, which extends the use of cyclic tetrapeptides to the class II HDAC isoforms. These findings highlight the persistent potential of cyclic tetrapeptides as epigenetic modulators and possible anticancer drug lead compounds.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Olsen
authors.forename: M Reza
authors.initials: MR
authors.lastname: Ghadiri
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D055808:Drug Discovery; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D019169:Jurkat Cells; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007527:Isoenzymes; D009842:Oligopeptides; D010456:Peptides, Cyclic; D006655:Histone Deacetylases
references.citation: Nat Chem Biol. 2006 Oct;2(10):551-8
references.pmid: 16921367
references.citation: Angew Chem Int Ed Engl. 2009;48(26):4718-24
references.pmid: 19267380
references.citation: J Biol Chem. 1993 Oct 25;268(30):22429-35
references.pmid: 8226751
references.citation: J Pept Sci. 2006 Jun;12(6):383-8
references.pmid: 16342331
references.citation: Chem Rev. 1997 Apr 1;97(2):411-448
references.pmid: 11848877
references.citation: Org Lett. 2008 Aug 21;10(16):3595-8
references.pmid: 18616341
references.citation: Nat Rev Cancer. 2006 Jan;6(1):38-51
references.pmid: 16397526
references.citation: Nature. 2007 May 10;447(7141):178-82
references.pmid: 17468743
references.citation: Cell. 2007 Feb 23;128(4):693-705
references.pmid: 17320507
references.citation: J Am Chem Soc. 2008 Feb 13;130(6):1806-7
references.pmid: 18205365
references.citation: J Med Chem. 2000 Dec 14;43(25):4919-22
references.pmid: 11124001
references.citation: J Am Chem Soc. 2009 Mar 4;131(8):3033-41
references.pmid: 19239270
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17335-40
references.pmid: 17956988
references.citation: J Med Chem. 2008 Mar 27;51(6):1505-29
references.pmid: 18247554
references.citation: J Am Chem Soc. 2008 Aug 20;130(33):11219-22
references.pmid: 18642817
references.citation: Chem Soc Rev. 2008 Jul;37(7):1402-13
references.pmid: 18568166
references.citation: Bioorg Med Chem Lett. 2007 May 15;17(10):2874-8
references.pmid: 17346959
references.citation: Bioorg Med Chem Lett. 2001 Jan 22;11(2):107-11
references.pmid: 11206438
references.citation: Cell. 2004 Nov 12;119(4):555-66
references.pmid: 15537544
references.citation: Bioorg Med Chem Lett. 2008 May 1;18(9):2982-4
references.pmid: 18397826
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9633-8
references.pmid: 18606987
references.citation: Nat Rev Drug Discov. 2006 Sep;5(9):769-84
references.pmid: 16955068
references.citation: Trends Genet. 2003 May;19(5):286-93
references.pmid: 12711221
references.citation: Angew Chem Int Ed Engl. 2005 May 20;44(21):3186-216
references.pmid: 15898057
references.citation: J Am Chem Soc. 2003 Jan 22;125(3):640-1
references.pmid: 12526657
references.citation: Nat Med. 2007 Nov;13(11):1299-307
references.pmid: 17922010
references.citation: Nat Rev Drug Discov. 2008 Oct;7(10):854-68
references.pmid: 18827828
references.citation: Structure. 2004 Jul;12(7):1325-34
references.pmid: 15242608
references.citation: Nat Rev Cancer. 2001 Dec;1(3):194-202
references.pmid: 11902574
references.citation: J Biol Chem. 2008 Dec 19;283(51):35402-9
references.pmid: 18953021
references.citation: Nature. 2007 Jun 14;447(7146):859-63
references.pmid: 17568747
references.citation: Nature. 1999 Sep 9;401(6749):188-93
references.pmid: 10490031
references.citation: Science. 1996 Apr 19;272(5260):408-11
references.pmid: 8602529
references.citation: Mol Cell. 2002 Jan;9(1):45-57
references.pmid: 11804585
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15064-9
references.pmid: 15477595
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4389-94
references.pmid: 12677000
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):87-92
references.pmid: 11134513
references.citation: J Med Chem. 2008 May 22;51(10):2898-906
references.pmid: 18412327
references.citation: Chemistry. 2007;13(14):4008-13
references.pmid: 17304598
references.citation: J Med Chem. 2004 Jun 3;47(12):2984-94
references.pmid: 15163181
references.citation: J Med Chem. 2006 Aug 10;49(16):4809-12
references.pmid: 16884291
references.citation: J Biol Chem. 2008 Sep 26;283(39):26694-704
references.pmid: 18614528
references.citation: Nature. 1991 Nov 7;354(6348):82-4
references.pmid: 1944576
references.citation: Nat Biotechnol. 2007 Jan;25(1):84-90
references.pmid: 17211407
references.citation: J Org Chem. 2006 Sep 1;71(18):6814-21
references.pmid: 16930031
references.citation: Angew Chem Int Ed Engl. 2006 Nov 20;45(45):7553-7
references.pmid: 16981208
references.citation: J Biol Chem. 2001 Sep 21;276(38):35826-35
references.pmid: 11466315
references.citation: J Am Chem Soc. 2009 Mar 4;131(8):2900-5
references.pmid: 19193120
references.citation: Cell. 2007 Mar 9;128(5):1003-12
references.pmid: 17350582
references.citation: Bioorg Med Chem. 2005 Sep 1;13(17):5145-53
references.pmid: 15993611
references.citation: Biochem Biophys Res Commun. 1983 Mar 16;111(2):398-403
references.pmid: 6132602
references.citation: Curr Opin Oncol. 2001 Nov;13(6):477-83
references.pmid: 11673688
references.citation: J Am Chem Soc. 2008 Feb 20;130(7):2184-94
references.pmid: 18217751
references.citation: J Am Chem Soc. 2007 Mar 14;129(10):3007-12
references.pmid: 17311384
references.citation: Bioorg Med Chem. 2007 Dec 15;15(24):7830-9
references.pmid: 17881232
references.citation: J Biol Chem. 2008 Apr 25;283(17):11355-63
references.pmid: 18285338
references.citation: J Med Chem. 2008 Aug 14;51(15):4370-3
references.pmid: 18642892
references.citation: Nat Chem Biol. 2008 Oct;4(10):590-7
references.pmid: 18800048
references.citation: ChemMedChem. 2007 Oct;2(10):1511-9
references.pmid: 17694590
references.citation: Angew Chem Int Ed Engl. 2008;47(34):6483-5
references.pmid: 18633950
references.citation: J Med Chem. 1987 Jan;30(1):71-8
references.pmid: 3806605
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1171-6
references.pmid: 17227860
references.citation: Nat Neurosci. 2006 Apr;9(4):519-25
references.pmid: 16501568
references.citation: Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7738-43
references.pmid: 18509061
references.citation: Org Lett. 2007 Mar 15;9(6):1105-8
references.pmid: 17311393
references.citation: Org Lett. 2009 Mar 19;11(6):1301-4
references.pmid: 19239241
references.citation: Biochemistry. 2008 Jun 10;47(23):6242-50
references.pmid: 18470998
references.citation: Cell. 2007 Nov 16;131(4):633-6
references.pmid: 18022353
references.citation: Anal Biochem. 2003 Oct 15;321(2):202-8
references.pmid: 14511685
references.citation: Antimicrob Agents Chemother. 2005 Aug;49(8):3302-10
references.pmid: 16048940
references.citation: Org Lett. 2008 Sep 4;10(17):3907-9
references.pmid: 18662003
references.citation: Nature. 2002 May 23;417(6887):455-8
references.pmid: 12024216
references.citation: Science. 2005 Jan 14;307(5707):269-73
references.pmid: 15653507
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13143-7
references.pmid: 8917558
references.citation: Bioorg Med Chem Lett. 2001 Jan 22;11(2):113-7
references.pmid: 11206439
references.citation: J Am Chem Soc. 2008 Jul 2;130(26):8455-9
references.pmid: 18507379
references.citation: J Comb Chem. 2003 Jan-Feb;5(1):33-40
references.pmid: 12523832
references.citation: J Biol Chem. 2002 Mar 15;277(11):9447-54
references.pmid: 11779848
references.citation: Org Lett. 2008 Sep 18;10(18):4021-4
references.pmid: 18707106
references.citation: Chem Biol. 2003 May;10(5):383-96
references.pmid: 12770821
references.citation: J Med Chem. 2004 Oct 7;47(21):5235-43
references.pmid: 15456267
references.citation: Angew Chem Int Ed Engl. 2006 Nov 20;45(45):7557-60
references.pmid: 16960909
references.citation: Chem Commun (Camb). 2002 Mar 7;(5):508-9
references.pmid: 12120564
references.citation: J Med Chem. 2006 Dec 28;49(26):7611-22
references.pmid: 17181145
references.citation: J Med Chem. 2007 Nov 1;50(22):5425-38
references.pmid: 17929798
references.citation: Cell. 2006 Jul 28;126(2):321-34
references.pmid: 16873063