title: Inhibitor of MYC identified in a Kröhnke pyridine library.
abstract: In a fluorescence polarization screen for the MYC-MAX interaction, we have identified a novel small-molecule inhibitor of MYC, KJ-Pyr-9, from a Kröhnke pyridine library. The Kd of KJ-Pyr-9 for MYC in vitro is 6.5 ± 1.0 nM, as determined by backscattering interferometry; KJ-Pyr-9 also interferes with MYC-MAX complex formation in the cell, as shown in a protein fragment complementation assay. KJ-Pyr-9 specifically inhibits MYC-induced oncogenic transformation in cell culture; it has no or only weak effects on the oncogenic activity of several unrelated oncoproteins. KJ-Pyr-9 preferentially interferes with the proliferation of MYC-overexpressing human and avian cells and specifically reduces the MYC-driven transcriptional signature. In vivo, KJ-Pyr-9 effectively blocks the growth of a xenotransplant of MYC-amplified human cancer cells.
authors.affiliation: Departments of Molecular and Experimental Medicine and.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Hart
authors.affiliation: Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Garner
authors.affiliation: Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Departments of Molecular and Experimental Medicine and.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Departments of Molecular and Experimental Medicine and.
authors.forename: Minghao
authors.initials: M
authors.lastname: Sun
authors.affiliation: Departments of Molecular and Experimental Medicine and.
authors.forename: Lynn
authors.initials: L
authors.lastname: Ueno
authors.affiliation: Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and.
authors.forename: Jin-Kyu
authors.initials: JK
authors.lastname: Rhee
authors.affiliation: Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Baksh
authors.affiliation: Institute of Biochemistry, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Eduard
authors.initials: E
authors.lastname: Stefan
authors.affiliation: Institute of Biochemistry, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Hartl
authors.affiliation: Institute of Biochemistry, University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Bister
authors.affiliation: Departments of Molecular and Experimental Medicine and pkvogt@scripps.edu kdjanda@scripps.edu.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Vogt
authors.affiliation: Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and pkvogt@scripps.edu kdjanda@scripps.edu.
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002642:Chick Embryo; D004353:Drug Evaluation, Preclinical; D005260:Female; D005454:Fluorescence Polarization; D016259:Genes, myc; D006801:Humans; D007368:Interferometry; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C000593138:KJ-Pyr-9; C499330:MAX protein, human; C489427:MYC protein, human; D046912:Multiprotein Complexes; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D011743:Pyrimidines
keywords: combinatorial library; gene signature; protein–protein interactions; transcriptional control; xenograft
references.citation: Curr Top Microbiol Immunol. 2011;348:1-23
references.pmid: 20827522
references.citation: Mol Cell Biol. 2006 Mar;26(6):2373-86
references.pmid: 16508012
references.citation: J Biopharm Stat. 2009 Sep;19(5):755-62
references.pmid: 20183441
references.citation: Proc Natl Acad Sci U S A. 1977 Oct;74(10):4320-4
references.pmid: 200913
references.citation: Nucleic Acids Res. 2001 Jan 15;29(2):397-406
references.pmid: 11139609
references.citation: Ther Clin Risk Manag. 2005 Jun;1(2):107-14
references.pmid: 18360550
references.citation: Curr Top Microbiol Immunol. 2011;348:151-72
references.pmid: 21046355
references.citation: Nat Genet. 2003 Jul;34(3):267-73
references.pmid: 12808457
references.citation: Cell. 2012 Mar 30;149(1):22-35
references.pmid: 22464321
references.citation: Curr Top Med Chem. 2011;11(3):258-80
references.pmid: 21320057
references.citation: Curr Top Microbiol Immunol. 2011;348:115-37
references.pmid: 20941592
references.citation: Cell. 2012 Sep 28;151(1):68-79
references.pmid: 23021216
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16916-21
references.pmid: 17942691
references.citation: Curr Opin Chem Biol. 2005 Jun;9(3):317-24
references.pmid: 15939335
references.citation: Curr Top Microbiol Immunol. 2011;348:139-49
references.pmid: 20680803
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14950-5
references.pmid: 9843996
references.citation: Chem Biol. 2006 Jul;13(7):745-51
references.pmid: 16873022
references.citation: PLoS One. 2011;6(10):e26057
references.pmid: 22039435
references.citation: Nature. 2008 Oct 2;455(7213):679-83
references.pmid: 18716624
references.citation: J Immunol Methods. 1994 Apr 15;170(2):211-24
references.pmid: 8157999
references.citation: PLoS One. 2011;6(7):e22284
references.pmid: 21811581
references.citation: Curr Top Microbiol Immunol. 2011;348:25-59
references.pmid: 20703966
references.citation: Nat Rev Drug Discov. 2004 Apr;3(4):301-17
references.pmid: 15060526
references.citation: Curr Opin Chem Biol. 2009 Jun;13(3):284-90
references.pmid: 19553156
references.citation: Proc Natl Acad Sci U S A. 1982 Dec;79(24):7824-7
references.pmid: 6961453
references.citation: Exp Cell Res. 2010 May 1;316(8):1429-37
references.pmid: 20382143
references.citation: Genes Dev. 2001 Aug 15;15(16):2023-30
references.pmid: 11511533
references.citation: Harvey Lect. 2000-2001;96:1-32
references.pmid: 12200869
references.citation: Nat Biotechnol. 2011 Apr;29(4):357-60
references.pmid: 21399645
references.citation: Genome Biol. 2003;4(10):R69
references.pmid: 14519204
references.citation: Curr Top Microbiol Immunol. 2006;302:145-67
references.pmid: 16620028
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5604-9
references.pmid: 19297618
references.citation: Virology. 1969 Sep;39(1):18-30
references.pmid: 4309068
references.citation: Cell. 2003 Jan 24;112(2):193-205
references.pmid: 12553908
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 18;110(25):10258-63
references.pmid: 23733953
references.citation: Cancer Res. 2006 May 1;66(9):4591-601
references.pmid: 16651409
references.citation: J Natl Cancer Inst Monogr. 1993;(15):141-7
references.pmid: 7912520
references.citation: Cell. 2012 Sep 28;151(1):56-67
references.pmid: 23021215
references.citation: Oncogene. 2003 Sep 18;22(40):6151-9
references.pmid: 13679853
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: Genes Dev. 2013 Mar 1;27(5):504-13
references.pmid: 23475959
references.citation: J Med Chem. 2006 Jan 26;49(2):656-63
references.pmid: 16420051
references.citation: Annu Rev Biophys Biomol Struct. 2004;33:199-223
references.pmid: 15139811
references.citation: Genes Dev. 1990 Oct;4(10):1677-87
references.pmid: 2123464
references.citation: Genes Cancer. 2010 Jun;1(6):650-659
references.pmid: 21132100
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3830-5
references.pmid: 11891322
references.citation: Genes Dev. 2011 May 1;25(9):907-16
references.pmid: 21478273
references.citation: Nat Med. 2011 Aug 07;17(9):1116-20
references.pmid: 21822287
references.citation: Bioorg Med Chem. 2013 Jul 15;21(14):4051-7
references.pmid: 23267671
references.citation: Science. 1991 Mar 8;251(4998):1211-7
references.pmid: 2006410
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7319-24
references.pmid: 11404481
references.citation: Proc Natl Acad Sci U S A. 2013 May 21;110(21):8531-6
references.pmid: 23657011
references.citation: Oncogene. 1999 May 13;18(19):2934-41
references.pmid: 10378690