title: Identification of substituted pyrimido[5,4-b]indoles as selective Toll-like receptor 4 ligands.
abstract: A cell-based high-throughput screen to identify small molecular weight stimulators of the innate immune system revealed substituted pyrimido[5,4-b]indoles as potent NFκB activators. The most potent hit compound selectively stimulated Toll-like receptor 4 (TLR4) in human and mouse cells. Synthetic modifications of the pyrimido[5,4-b]indole scaffold at the carboxamide, N-3, and N-5 positions revealed differential TLR4 dependent production of NFκB and type I interferon associated cytokines, IL-6 and interferon γ-induced protein 10 (IP-10) respectively. Specifically, a subset of compounds bearing phenyl and substituted phenyl carboxamides induced lower IL-6 release while maintaining higher IP-10 production, skewing toward the type I interferon pathway. Substitution at N-5 with short alkyl substituents reduced the cytotoxicity of the leading hit compound. Computational studies supported that active compounds appeared to bind primarily to MD-2 in the TLR4/MD-2 complex. These small molecules, which stimulate innate immune cells with minimal toxicity, could potentially be used as adjuvants or immune modulators.
authors: Moores Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0695, USA.
authors: Michael
authors: M
authors: Chan
authors: Tomoko
authors: T
authors: Hayashi
authors: Richard D
authors: RD
authors: Mathewson
authors: Afshin
authors: A
authors: Nour
authors: Yuki
authors: Y
authors: Hayashi
authors: Shiyin
authors: S
authors: Yao
authors: Rommel I
authors: RI
authors: Tawatao
authors: Brian
authors: B
authors: Crain
authors: Igor F
authors: IF
authors: Tsigelny
authors: Valentina L
authors: VL
authors: Kouznetsova
authors: Karen
authors: K
authors: Messer
authors: Minya
authors: M
authors: Pu
authors: Maripat
authors: M
authors: Corr
authors: Dennis A
authors: DA
authors: Carson
authors: Howard B
authors: HB
authors: Cottam
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000819:agonists / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D007211:Indoles; D015850:Interleukin-6; D016209:Interleukin-8; D008024:Ligands; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D016328:NF-kappa B; D011743:Pyrimidines; D051197:Toll-Like Receptor 4
references: J Pharm Sci. 1976 May;65(5):660-4
references: 932932
references: Cancer Immunol Immunother. 2010 Jan;59(1):35-46
references: 19449004
references: Nature. 2000 Dec 7;408(6813):740-5
references: 11130078
references: Nat Immunol. 2005 Jun;6(6):565-70
references: 15895089
references: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W445-9
references: 20444869
references: Int Immunol. 2004 Jul;16(7):961-9
references: 15184344
references: Proc Natl Acad Sci U S A. 2003 May 27;100(11):6646-51
references: 12738885
references: Stat Med. 2012 Dec 30;31(30):4175-89
references: 22763983
references: J Immunol. 2002 Dec 15;169(12):6668-72
references: 12471095
references: Bioconjug Chem. 2009 Jun;20(6):1194-200
references: 19445505
references: Science. 2007 Jun 15;316(5831):1628-32
references: 17569868
references: J Immunol. 2001 Nov 15;167(10):5887-94
references: 11698465
references: J Biol Chem. 2006 Mar 3;281(9):5484-91
references: 16407172
references: J Immunol. 2006 Jan 1;176(1):157-64
references: 16365406
references: Nature. 1997 Jul 24;388(6640):394-7
references: 9237759
references: J Immunol. 2009 Oct 15;183(8):5138-45
references: 19783674
references: Nat Rev Immunol. 2002 Oct;2(10):725-34
references: 12360211
references: Mamm Genome. 2006 May;17(5):398-406
references: 16688530
references: J Biol Chem. 2011 Sep 2;286(35):30393-30400
references: 21730052
references: J Immunol. 2005 Oct 1;175(7):4490-8
references: 16177092
references: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):3990-5
references: 17360465
references: J Biol Chem. 2010 Sep 3;285(36):27935-43
references: 20592019
references: Nature. 2009 Apr 30;458(7242):1191-5
references: 19252480
references: Brain Behav Immun. 2010 Jan;24(1):83-95
references: 19679181
references: Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1828-33
references: 16446426
references: Science. 1990 Sep 21;249(4975):1431-3
references: 1698311
references: Proc Natl Acad Sci U S A. 2012 May 8;109(19):7421-6
references: 22532668
references: Chembiochem. 2011 Aug 16;12(12):1827-31
references: 21678541
references: J Exp Med. 1999 Jun 7;189(11):1777-82
references: 10359581
references: J Biol Chem. 2008 Oct 10;283(41):27916-27926
references: 18650420
references: Infect Immun. 2001 Oct;69(10):6156-64
references: 11553555
references: Neuroscience. 2010 Jun 30;168(2):551-63
references: 20381591
references: Curr Top Microbiol Immunol. 2011;349:115-43
references: 20848362
references: Nat Immunol. 2002 Jul;3(7):667-72
references: 12055629
references: J Immunol. 2008 Jul 15;181(2):1245-54
references: 18606678
references: Immunity. 2010 Oct 29;33(4):492-503
references: 21029960