Novel IKK Inhibitors: β‐Carbolines.

Castro, Alfredo; Dang, Lenny; Soucy, François; Grenier, Louis; Mazdiyasni, Hormoz; Hottelet, Maria; Parent, Lana; Pien, Christine; Palombella, Vito J.; Adams, Julian

doi:10.1002/chin.200342147

Cited by 64 publications

(90 citation statements)

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“…The selective inhibition of the two catalytic subunits of the IKK complex or the individual NF-κB subunits represents the ultimate goal of drug design. Accordingly, a wide range of selective IKK inhibitors are now being developed, such as, SPC-839, PS-1145, BMS-345541, and SC-514 [18,20,73,103,164].…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

NF‐κB as a potential molecular target for cancer therapy

et al. 2007

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Abstract. Nuclear factor κB (NF-κB), a transcription factor, plays an important role in carcinogenesis as well as in the regulation of immune and inflammatory responses. NF-κB induces the expression of diverse target genes that promote cell proliferation, regulate apoptosis, facilitate angiogenesis and stimulate invasion and metastasis. Furthermore, many cancer cells show aberrant or constitutive NF-κB activation which mediates resistance to chemo-and radio-therapy. Therefore, the inhibition of NF-κB activation and its signaling pathway offers a potential cancer therapy strategy. In addition, recent studies have shown that NF-κB can also play a tumor suppressor role in certain settings. In this review, we focus on the role of NF-κB in carcinogenesis and the therapeutic potential of targeting NF-κB in cancer therapy.Keywords: NF-κB, NF-κB inhibitor, carcinogenesis, cancer therapy Structure, function and regulation of NF-κBNuclear factor-κB (NF-κB) was first identified in 1986 as a transcription factor that binds to a 10 bp DNA element in kappa immunoglobulin light-chain enhancer in B cells [128]. The mammalian NF-κB family consists of 5 members: NF-κB1 (p50/p105), NF-κB2 (p52/p100), c-Rel, RelA (p65) and RelB (Fig. 1). RelA, c-Rel and RelB are synthesized in their mature forms and contain a transactivation domain that interacts with the transcriptional apparatus. On the other hand, NF-κB1 (p50/p105) and NF-κB2 (p52/p100) are synthesized in precursor forms (p100 and p105) which contain C-terminal ankyrin repeats that are proteolysed by the proteasome resulting in the production of mature proteins (p50 and p52). Both p50 and p52 contain a DNA binding domain but lack a transactivation domain. NF-κB proteins exist in unstimulated cells as homo-or heterodimers bound to IκB proteins. Whereas RelB forms only heterodimers, all the other proteins can form both homo-and heterodimers. NF-κB proteins are characterized by the presence of a highly conserved 300 amino acid Rel homology domain that is located toward the N terminus of the protein, and which is responsible for DNA binding, dimerization, and interaction with specific inhibitory factors known as IκB proteins [7,36].

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Section: Conclusion and Future Prospectsmentioning

confidence: 99%

NF‐κB as a potential molecular target for cancer therapy

et al. 2007

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“…The brominated derivative 11 of nostocarboline as well as the precursor utilized for feeding were prepared starting from tryptamine 7 following literature procedures. [17][18][19][20] 1,2,3,4-Tetrahydro-"-carboline 8 was obtained via a Pictet-Spengler reaction between 7 and glyoxylic acid followed by an acidic decarboxylation. [17] Compound 8 was then oxidized with Pd/C to give norharmane 9 in high yield (98%).…”

Section: Resultsmentioning

confidence: 99%

“…[17] Compound 8 was then oxidized with Pd/C to give norharmane 9 in high yield (98%). [18,19] Bromination of 9 with NBS afforded eudistomin N (10) in good yield (75%). [20] Finally, the methylation of compound 10 to Br-nostocarboline (11) with CH3I was realized according to the procedure developed for the total synthesis of nostocarboline.…”

Section: Resultsmentioning

confidence: 99%

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Directed Biosynthesis of Phytotoxic Alkaloids in the Cyanobacterium Nostoc 78–12A

Portmann¹,

Prestinari²,

Myers³

et al. 2009

ChemBioChem

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“…Most common IKK inhibitors, which includes b-carbolin (PS-1145) and quinazoline (SPC-839) exert their effect by inhibiting incorporation of ATP into IKK. 91,92 ACHP [2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile] also exerts its effect by competing with ATP for incorporation to IKK. 93 BMS-345541, which is a quinoxaline derivative, inhibits kinase activity by an allosteric effect without affecting ATP binding.…”

Section: Ikk Inhibitorsmentioning

confidence: 99%

Molecularly-Targeted Strategy and NF-^|^kappa;B in Lymphoid Malignancies

Horie

2013

J Clin Exp Hematopathol

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Molecularly-targeted therapy is a promising strategy for the treatment of cancer. Nuclear factor (NF)-kB is a transcription factor that is constitutively activated in various lymphoid malignancies and may therefore be a good therapeutic target. Lymphoid malignancies arise from different stages of normal lymphocyte differentiation and acquire distinct pathways for constitutive NF-kB activation. However, no NF-kB inhibitor has yet been successfully applied in clinical medicine. This review focuses on the concept of molecularly-targeted therapeutics with small molecule drugs, molecular mechanisms of constitutive NF-kB activation in lymphoid malignancies, and the development of NF-kB inhibitors. A future perspective regarding the development of NF-kB inhibitors is also included. 〔J Clin Exp Hematop 53(3) : 185-195, 2013〕

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Novel IKK Inhibitors: β‐Carbolines.

Cited by 64 publications

References 1 publication

NF‐κB as a potential molecular target for cancer therapy

NF‐κB as a potential molecular target for cancer therapy

Directed Biosynthesis of Phytotoxic Alkaloids in the Cyanobacterium Nostoc 78–12A

Molecularly-Targeted Strategy and NF-^|^kappa;B in Lymphoid Malignancies

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