Discovery of quinazolines as a novel structural class of potent inhibitors of NF-κB activation

Tobe, Masanori; Isobe, Yoshiaki; Tomizawa, Hideyuki; Nagasaki, Takahiro; Takahashi, Hirotada; Fukazawa, Tominaga; Hayashi, Hideya

doi:10.1016/s0968-0896(02)00440-6

Cited by 153 publications

(119 citation statements)

References 31 publications

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“…45 In accordance, we found that NF-kB exhibited constitutive nuclear localization in the SeAx cell line (Figure 3e) and that an inhibitor of NF-kB transcriptional activation 46 (NF-kBI) induced dose-dependent growth arrest in the SeAx cells (Figure 8a). Given previous findings that wt FOXP3 inhibits NF-kB activity, 24 it was interesting to address whether the low molecular splice forms of FOXP3 also inhibit NF-kB transcriptional activity.…”

Section: Foxp3 Wt and Splice Forms Have Different Effects On Nf-kb Acsupporting

confidence: 76%

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

et al. 2008

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Sé zary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-b and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-jB (NF-jB) activity in reporter assays which is in keeping with a constitutive NF-jB activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease.

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Section: Foxp3 Wt and Splice Forms Have Different Effects On Nf-kb Acsupporting

confidence: 76%

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

et al. 2008

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“…This is demonstrated in supershift assays including antibodies for the NFjB subunits p50 (NFjB1) and p52 (NFjB2) where NFjB signals were abolished while the NOTCH2 complex remained unchanged (Fig 4A). Incubation of PMA-stimulated CLL cells with the NFjB transactivation inhibitor 6-Amino-4-(4-phenoxyphenyl-ethylamino) quinazoline (Tobe et al, 2003) completely blocked DNA-bound NFjB complexes within 4 h whereas NOTCH2 complexes were unaffected (Fig 4B). In contrast, short time exposure to gliotoxin inhibited the formation of NOTCH2 complexes but had no effect on NFjB binding in CLL cells (Fig 4B).…”

Section: Gliotoxin Induces Apoptosis In Cll Cells Independent Of Nfjbmentioning

confidence: 92%

Gliotoxin is a potent NOTCH2 transactivation inhibitor and efficiently induces apoptosis in chronic lymphocytic leukaemia (CLL) cells

et al. 2012

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SummaryChronic lymphocytic leukaemia (CLL) cells express constitutively activated NOTCH2 in a protein kinase C (PKC)-dependent manner. The transcriptional activity of NOTCH2 correlates not only with the expression of its target gene FCER2 (CD23) but is also functionally linked with CLL cell viability. In the majority of CLL cases, DNA-bound NOTCH2 complexes are less sensitive to the c-secretase inhibitor (GSI) DAPT. Therefore, we searched for compounds that interfere with NOTCH2 signalling at the transcription factor level. Using electrophoretic mobility shift assays (EMSA), we identified the Aspergillum-derived secondary metabolite gliotoxin as a potent NOTCH2 transactivation inhibitor. Gliotoxin completely blocked the formation of DNA-bound NOTCH2 complexes in CLL cells independent of their sensitivity to DAPT. The inhibition of NOTCH2 signalling by gliotoxin was associated with down regulation of CD23 (FCER) expression and induction of apoptosis. Short time exposure of CLL cells indicated that the early apoptotic effect of gliotoxin is independent of proteasome regulated nuclear factor jB activity, and is associated with up regulation of NOTCH3 and NR4A1 expression. Gliotoxin could overcome the supportive effect of primary bone marrow stromal cells in an ex vivo CLL microenvironment model. In conclusion, we identified gliotoxin as a potent NOTCH2 inhibitor with a promising therapeutic potential in CLL.

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“…Inhibitors. The NF-B inhibitors SN50 [6-amino-4-(4-phenoxyphenylethylamino)quinazoline] (34) and quinazoline (56) were purchased from Calbiochem (San Diego, CA), and TPCK (N-␣-p-tosyl-L-phenylalanine chloromethyl ketone) (7) was purchased from Sigma-Aldrich (St. Louis, MO). Chloroquine and the MyD88 homodimerization inhibitory peptide set were purchased from SigmaAldrich and Imgenex (San Diego, CA), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…SN50 is a cell-permeant peptide that inhibits the translocation of the active NF-B complex into the nucleus (34). Quinazoline inhibits NF-B transcriptional activation (56). TPCK, a proteasome inhibitor, inhibits IB-␣ degradation (20).…”

Section: Campylobacter-induced Il-8 Secretion In Human Intestinal Epimentioning

confidence: 99%

Campylobacter-Induced Interleukin-8 Secretion in Polarized Human Intestinal Epithelial Cells RequiresCampylobacter-Secreted Cytolethal Distending Toxin- and Toll-Like Receptor-Mediated Activation of NF-κB

Zheng¹,

Meng²,

Zhao

et al. 2008

Infect Immun

113

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Discovery of quinazolines as a novel structural class of potent inhibitors of NF-κB activation

Cited by 153 publications

References 31 publications

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

Gliotoxin is a potent NOTCH2 transactivation inhibitor and efficiently induces apoptosis in chronic lymphocytic leukaemia (CLL) cells

Campylobacter-Induced Interleukin-8 Secretion in Polarized Human Intestinal Epithelial Cells RequiresCampylobacter-Secreted Cytolethal Distending Toxin- and Toll-Like Receptor-Mediated Activation of NF-κB

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