title: A complex task? Direct modulation of transcription factors with small molecules.
abstract: Transcription factors with aberrant activity in disease are promising yet untested targets for therapeutic development, particularly in oncology. Directly inhibiting or activating the function of a transcription factor requires specific disruption or recruitment of protein-protein or protein-DNA interactions. The discovery or design of small molecules that specifically modulate these interactions has thus far proven to be a significant challenge and the protein class is often perceived to be 'undruggable.' This review will summarize recent progress in the development of small-molecule probes of transcription factors and provide evidence to challenge the notion that this important protein class is chemically intractable.
authors.affiliation: Broad Institute of Harvard and MIT, Chemical Biology Program, 7 Cambridge Center, Cambridge, MA 02142, USA. koehler@broadinstitute.org
authors.forename: Angela N
authors.initials: AN
authors.lastname: Koehler
mesh_terms: D016503:Drug Delivery Systems; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors; D004364:Pharmaceutical Preparations / Q000737:chemistry; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D015514:Oncogene Proteins, Fusion; D004364:Pharmaceutical Preparations; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 13;106(2):450-5
references.pmid: 19129502
references.citation: Nat Med. 2009 Jul;15(7):750-6
references.pmid: 19584866
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3830-5
references.pmid: 11891322
references.citation: J Cell Mol Med. 2009 Sep;13(9A):2780-6
references.pmid: 19674190
references.citation: ChemMedChem. 2007 May;2(5):627-30
references.pmid: 17315254
references.citation: Science. 2008 Dec 19;322(5909):1839-42
references.pmid: 19056937
references.citation: Curr Opin Genet Dev. 2007 Feb;17(1):78-83
references.pmid: 17210248
references.citation: Oncol Rep. 2008 Mar;19(3):825-30
references.pmid: 18288422
references.citation: ACS Chem Biol. 2007 Aug 17;2(8):561-71
references.pmid: 17708671
references.citation: Chem Biol. 2004 May;11(5):639-46
references.pmid: 15157874
references.citation: J Med Chem. 2008 Oct 23;51(20):6512-30
references.pmid: 18785725
references.citation: Oncogene. 1999 May 13;18(19):3004-16
references.pmid: 10378696
references.citation: Nat Cell Biol. 2000 Feb;2(2):84-9
references.pmid: 10655587
references.citation: Chembiochem. 2009 Aug 17;10(12):1959-64
references.pmid: 19644994
references.citation: Curr Opin Chem Biol. 2008 Aug;12(4):464-71
references.pmid: 18706517
references.citation: J Am Chem Soc. 2003 Jul 16;125(28):8420-1
references.pmid: 12848532
references.citation: Chem Biol. 2006 Jul;13(7):745-51
references.pmid: 16873022
references.citation: J Am Chem Soc. 2009 Jun 3;131(21):7390-401
references.pmid: 19432426
references.citation: Cell Cycle. 2006 Oct;5(19):2191-4
references.pmid: 17012843
references.citation: Chem Biol. 2008 Nov 24;15(11):1149-55
references.pmid: 19022175
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17910-5
references.pmid: 19805192
references.citation: Annu Rev Genet. 1998;32:495-519
references.pmid: 9928489
references.citation: J Biol Chem. 2005 Dec 30;280(52):43048-55
references.pmid: 16263725
references.citation: Blood. 2007 May 15;109(10):4432-40
references.pmid: 17244680
references.citation: Angew Chem Int Ed Engl. 2006 Jul 10;45(28):4552-60
references.pmid: 16819755
references.citation: Nature. 2009 Nov 12;462(7270):182-8
references.pmid: 19907488
references.citation: ACS Chem Biol. 2008 May 16;3(5):282-6
references.pmid: 18484708
references.citation: Cancer Res. 2008 Aug 1;68(15):6292-9
references.pmid: 18676853
references.citation: Trends Biotechnol. 2006 Oct;24(10):435-42
references.pmid: 16876893
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):227-32
references.pmid: 14694204
references.citation: Bioorg Med Chem Lett. 2008 Jan 1;18(1):391-5
references.pmid: 18006313
references.citation: J Biol Chem. 2005 Sep 23;280(38):32979-88
references.pmid: 16046414
references.citation: J Am Chem Soc. 2009 Dec 9;131(48):17647-54
references.pmid: 19950993
references.citation: Proc Natl Acad Sci U S A. 2007 May 1;104(18):7391-6
references.pmid: 17463090
references.citation: Prostate. 2008 Feb 15;68(3):269-80
references.pmid: 18163422
references.citation: Cell Stem Cell. 2009 May 8;4(5):416-26
references.pmid: 19427291
references.citation: Nat Rev Cancer. 2002 Oct;2(10):740-9
references.pmid: 12360277
references.citation: Curr Opin Chem Biol. 2005 Oct;9(5):467-74
references.pmid: 16122970
references.citation: Chem Biol. 2007 Oct;14(10):1186-97
references.pmid: 17961830
references.citation: ACS Chem Biol. 2007 Dec 21;2(12):787-98
references.pmid: 18154266
references.citation: J Med Chem. 2009 Mar 12;52(5):1247-50
references.pmid: 19215087
references.citation: Cell. 2003 Jan 24;112(2):193-205
references.pmid: 12553908
references.citation: Science. 2002 Feb 1;295(5556):813-8
references.pmid: 11823631
references.citation: Proc Natl Acad Sci U S A. 2005 Mar 29;102(13):4700-5
references.pmid: 15781862
references.citation: Anal Biochem. 2005 May 15;340(2):259-71
references.pmid: 15840499
references.citation: J Med Chem. 2009 Jul 9;52(13):3892-901
references.pmid: 19469546
references.citation: Bioorg Med Chem. 2006 Apr 15;14(8):2660-73
references.pmid: 16384710
references.citation: Bioorg Med Chem Lett. 2009 Nov 1;19(21):6038-41
references.pmid: 19800226
references.citation: Oncogene. 2003 Sep 18;22(40):6151-9
references.pmid: 13679853
references.citation: Cancer Cell. 2004 Jul;6(1):33-43
references.pmid: 15261140
references.citation: Bioorg Med Chem Lett. 2007 Apr 1;17(7):1875-8
references.pmid: 17336521
references.citation: Chem Soc Rev. 2008 Jul;37(7):1385-94
references.pmid: 18568164
references.citation: Curr Opin Struct Biol. 2004 Jun;14(3):283-91
references.pmid: 15193307
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17622-7
references.pmid: 15585582
references.citation: Genome Res. 2004 Apr;14(4):580-90
references.pmid: 15059999
references.citation: Cancer Chemother Pharmacol. 2009 Mar;63(4):615-25
references.pmid: 18509642
references.citation: Drug Discov Today. 2007 Jun;12(11-12):440-5
references.pmid: 17532527
references.citation: Genes Dev. 2006 Jun 1;20(11):1458-69
references.pmid: 16751183
references.citation: Bioorg Med Chem Lett. 2009 Feb 1;19(3):807-10
references.pmid: 19114306
references.citation: Chem Biol. 2006 Nov;13(11):1235-42
references.pmid: 17114005
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12682-7
references.pmid: 15314234
references.citation: PLoS One. 2009;4(5):e5609
references.pmid: 19440305
references.citation: Bioorg Med Chem. 2009 Oct 1;17(19):7021-30
references.pmid: 19729315
references.citation: Angew Chem Int Ed Engl. 2007;46(28):5352-5
references.pmid: 17568465
references.citation: ACS Chem Biol. 2009 May 15;4(5):335-44
references.pmid: 19348463
references.citation: Nature. 2001 Feb 15;409(6822):860-921
references.pmid: 11237011
references.citation: ACS Chem Biol. 2009 Jun 19;4(6):435-40
references.pmid: 19441848
references.citation: Nat Genet. 2009 Mar;41(3):286-8
references.pmid: 19182804
references.citation: Mol Cancer Ther. 2007 Sep;6(9):2399-408
references.pmid: 17876039
references.citation: J Am Chem Soc. 2009 Dec 23;131(50):18078-88
references.pmid: 20000859
references.citation: Bioorg Med Chem. 2008 Dec 1;16(23):10075-84
references.pmid: 18976929
references.citation: Chembiochem. 2008 Sep 1;9(13):2039-44
references.pmid: 18677740
references.citation: Science. 2009 Apr 10;324(5924):213-5
references.pmid: 19359579
references.citation: Angew Chem Int Ed Engl. 2007;46(16):2865-8
references.pmid: 17351994
references.citation: Cancer Res. 2005 Oct 1;65(19):9047-55
references.pmid: 16204079
references.citation: J Clin Invest. 2000 Nov;106(9):1071-5
references.pmid: 11067859
references.citation: Chembiochem. 2008 Mar 25;9(5):723-7
references.pmid: 18247434
references.citation: Nat Rev Cancer. 2007 Apr;7(4):233-45
references.pmid: 17361217
references.citation: Cell Cycle. 2006 Aug;5(16):1847-53
references.pmid: 16861921
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6344-9
references.pmid: 16606833