title: Discovery of substituted 4-aminoquinazolines as selective Toll-like receptor 4 ligands.
abstract: The Toll-like receptors (TLRs) are critical components of the innate immune system that regulate immune recognition in part through NF-κB activation. A human cell-based high throughput screen (HTS) revealed substituted 4-aminoquinazolines to be small molecular weight activators of NF-κB. The most potent hit compound predominantly stimulated through the human TLR4/MD2 complex, and had less activity with the mouse TLR4/MD2. There was no activity with other TLRs and the TLR4 activation was MD-2 dependent and CD14 independent. Synthetic modifications of the quinazoline scaffold at the 2 and 4 positions revealed trends in structure-activity relationships with respect to TLR dependent production of the NF-κB associated cytokine IL-8 in human peripheral blood mononuclear cells, as well as IL-6 in mouse antigen presenting cells. Furthermore, the hit compound in this series also activated the interferon signaling pathway resulting in type I interferon production. Substitution at the O-phenyl moiety with groups such as bromine, chlorine and methyl resulted in enhanced immunological activity. Computational studies indicated that the 4-aminoquinazoline compounds bind primarily to human MD-2 in the TLR4/MD-2 complex. These small molecules, which preferentially stimulate human rather than mouse innate immune cells, may be useful as adjuvants or immunotherapeutic agents.
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States.
authors.forename: Afshin
authors.initials: A
authors.lastname: Nour
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Chan
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States.
authors.forename: Shiyin
authors.initials: S
authors.lastname: Yao
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States.
authors.forename: Rommel I
authors.initials: RI
authors.lastname: Tawatao
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Crain
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States; San Diego Supercomputer Center, and University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States; Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States.
authors.forename: Igor F
authors.initials: IF
authors.lastname: Tsigelny
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States; San Diego Supercomputer Center, and University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States.
authors.forename: Valentina L
authors.initials: VL
authors.lastname: Kouznetsova
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States.
authors.forename: Alast
authors.initials: A
authors.lastname: Ahmadiiveli
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: Messer
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States.
authors.forename: Minya
authors.initials: M
authors.lastname: Pu
authors.affiliation: Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663, United States.
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carson
authors.affiliation: Moores Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093-0819, United States.
authors.forename: Howard B
authors.initials: HB
authors.lastname: Cottam
mesh_terms: D000818:Animals; D057166:High-Throughput Screening Assays; D006801:Humans; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism*; D011799:Quinazolines / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: C573775:4-aminoquinazoline; D015850:Interleukin-6; D016209:Interleukin-8; D008024:Ligands; D016328:NF-kappa B; D011799:Quinazolines; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
keywords: 4-Aminoquinazolines; Innate immune response; MD-2; NF-κB activation; Toll-like receptor 4