A new small molecule that directly inhibits the DNA binding of NF-κB

Kobayashi, Tomomi; Yoshimori, Atsushi; Kino, Katsuhito; Komori, Rie; Miyazawa, Hiroshi; Tanuma, Sei-ich

doi:10.1016/j.bmc.2009.05.030

Cited by 10 publications

(9 citation statements)

References 32 publications

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“…15) However, the present structure-activity relationship data indicate that the N-H hydrogen is not important, and that the whole 2,4-dichloro-1,3,5-triazine substructure is required Chart 1. Synthesis of Pyrimidine Derivatives for inhibitory activity of NI241.…”

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confidence: 60%

Synthesis and Structure–Activity Relationship Study of Triazine-Based Inhibitors of the DNA Binding of NF-κB

et al. 2014

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Nuclear transcription factor nuclear factor-kappa B (NF-κB) has diverse pathophysiological functions, and NF-κB inhibitors are considered to be candidates for multiple therapeutic applications. We previously reported a novel triazine-based NF-κB inhibitor, 2-anilino-4,6-dichloro-1,3,5-triazine (NI241), that directly inhibits DNA binding of NF-κB. Here, we report synthesis of a series of triazine derivatives and evaluation of their structure-activity relationships for NF-κB inhibition. We found that 2-amino-4,6-dichloro-1,3,5-triazine substructure is essential for the inhibitory activity of the lead compound NI241, and modification of NI241 by introduction of an m-methoxy substituent on the phenyl ring afforded the more potent derivative 28. The structure-activity relationships identified in this study suggested a possible mechanism of irreversible NF-κB inhibition by NI241, and should be helpful in the design of other NF-κB inhibitors.

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confidence: 60%

Synthesis and Structure–Activity Relationship Study of Triazine-Based Inhibitors of the DNA Binding of NF-κB

et al. 2014

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“…Another flavonoid, quercetin interfered with cell cycle progression and induced apoptosis in HeLa cells by inhibiting NF-κB activity [ 42 ]. Small molecule inhibitor screenings have also been effective in detecting compounds like N1241, which inhibits the ability of NF-κB to bind to DNA and interferes with its activity [ 43 ]. Additionally, drugs like bortezemib and thalidomide, which are approved by the US Food and Drug Administration (FDA) for the treatment of multiple myeloma, may also function, in part, by inhibiting NF-κB activity [ 44 , 45 ].…”

Section: Introductionmentioning

confidence: 99%

Critical role of NF-κB in pancreatic cancer

et al. 2014

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, and in spite of intense efforts there are limited therapeutic options for patients with PDAC. PDACs harbor a high frequency of Kras mutations and other driver mutations that lead to altered signaling pathways and contribute to therapeutic resistance. Importantly, constitutive activation of nuclear factor κB (NF-κB) is frequently observed in PDAC. An increasing body of evidence suggests that both classical and non-classical NF-κB pathways play a crucial role in PDAC development and progression. In this review, we update the most recent advances regarding different aspects of NF-κB involvement in PDAC development and progression, emphasizing its potential as a therapeutic target and the need to discover pathway-specific cytosolic NF-κB regulators which could be used to design novel therapeutic strategies for PDAC.

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“…To determine whether AIP6 has the ability to bind with κB elements, we designed an experiment using an ELISA-based Transfactor p65 kit (Active Motif, Carlsbad, CA). About 30 µl of binding buffer (Active Motif) containing AIP6 or NCP at various concentrations (25,50,100,200, and 400 μmol/l) was added to each well of the corresponding microtiter plate coated with an oligonucleotide containing the κB site of the immunoglobulin light chain gene promoter (GGGACTTTCC) and incubated for 30 minutes at room temperature. After washing three times with binding buffer, 30 μl binding buffer and 20 μl complete lysis buffer (Active Motif) containing 2.5 μg Jurkat nuclear extract (TPA + calcium ionophore) were added to the corresponding microtiter plate.…”

Section: Elisa-based Nf-κb P65 Transfactor Assaymentioning

confidence: 99%

“…To detect the inhibitory effect of AIP6 on the binding activity of NF-κB, another experiment was performed. To detect the binding activity of AIP6 to p65, 30 μl binding buffer containing AIP6 or NCP at various concentrations (25,50,100,200, and 400 μmol/l) was mixed with 20 μl complete lysis buffer containing 2.5 μg Jurkat nuclear extract and incubated for 30 minutes at room temperature. The mixtures were then added to the corresponding microtiter plate, and the plate was incubated for 1 hour at room temperature on a rocking platform.…”

Section: Elisa-based Nf-κb P65 Transfactor Assaymentioning

confidence: 99%

A Cell-penetrating Peptide Suppresses Inflammation by Inhibiting NF-κB Signaling

Wang

Xia

et al. 2011

Molecular Therapy

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Nuclear factor-κB (NF-κB) is a central regulator of immune response and a potential target for developing anti-inflammatory agents. Mechanistic studies suggest that compounds that directly inhibit NF-κB DNA binding may block inflammation and the associated tissue damage. Thus, we attempted to discover peptides that could interfere with NF-κB signaling based on a highly conserved DNA-binding domain found in all NF-κB members. One such small peptide, designated as anti-inflammatory peptide-6 (AIP6), was characterized in the current study. AIP6 directly interacted with p65 and displayed an intrinsic cell-penetrating property. This peptide demonstrated significant anti-inflammatory effects in vitro and in vivo. In vitro, AIP6 inhibited the DNA-binding and transcriptional activities of the p65 NF-κB subunit as well as the production of inflammatory mediators in macrophages upon stimulation. Local administration of AIP6 significantly inhibited inflammation induced by zymosan in mice. Collectively, our results suggest that AIP6 is a promising lead peptide for the development of specific NF-κB inhibitors as potential anti-inflammatory agents.

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A new small molecule that directly inhibits the DNA binding of NF-κB

Cited by 10 publications

References 32 publications

Synthesis and Structure–Activity Relationship Study of Triazine-Based Inhibitors of the DNA Binding of NF-κB

Synthesis and Structure–Activity Relationship Study of Triazine-Based Inhibitors of the DNA Binding of NF-κB

Critical role of NF-κB in pancreatic cancer

A Cell-penetrating Peptide Suppresses Inflammation by Inhibiting NF-κB Signaling

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