Discovery of 6-Aryl-7-alkoxyisoquinoline Inhibitors of IκB Kinase-β (IKK-β)

Christopher, John; Bamborough, Paul; Alder, Catherine M.; Campbell, Amanda; Cutler, Geoffrey J.; Down, Kenneth; Hamadi, Ahmed M.; Jolly, Adrian M.; Kerns, Jeffrey K.; Lucas, Fiona; Mellor, Geoffrey W.; Miller, David D.; Morse, Mary A.; Pancholi, Kiritkant D.; Rumsey, William L.; Solanke, Yemisi; Williamson, Rick

doi:10.1021/jm9000117

Cited by 31 publications

(24 citation statements)

References 9 publications

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“…41,42 The phase I clinical trial of topical formulation of IMD-0354 for treatment of atopic dermatitis has been successfully completed. Other synthetic IKK inhibitors, including S1627, 43 2-benzamido-pyrimidines, 44 2-amino-3,5-diarylbenzamides, 45,46 6-aryl-7-alkoxyisoquinolines, 47 4-phenyl-7-azaindoles, 48 PHA-408 49,50 and PF-184, 50 have been reported.…”

Section: Synthetic Ikk Inhibitorsmentioning

confidence: 99%

Chemical biology of inflammatory cytokine signaling

Kataoka

2009

J Antibiot

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Pro-inflammatory cytokines, such as tumor necrosis factor-a and interleukin-1, trigger the signal transduction pathway leading to the activation of the transcription factor, nuclear factor-jB (NF-jB). NF-jB induces a large number of target genes involved in many biological processes, such as inflammation, immunity, cell survival, cell death and carcinogenesis. As therapeutic agents for inflammatory diseases and cancer, as well as bioprobes for the characterization of intracellular biological response and cell function, a large number of natural and synthetic small molecules have been identified to inhibit the activation of the NF-jB signaling pathway. This review focuses on recent progress in the identification and biological properties of small molecules targeting the NF-jB signaling pathway induced by pro-inflammatory cytokines.

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Section: Synthetic Ikk Inhibitorsmentioning

confidence: 99%

Chemical biology of inflammatory cytokine signaling

Kataoka

2009

J Antibiot

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“…Recently, GlaxoSmithKline disclosed an isoquinoline class of IKK inhibitor [140]. The series emerged from a library which directed chemical diversity towards the hinge region of the IKK ATP binding site.…”

Section: Quinolines and Isoquinolinesmentioning

confidence: 99%

Progress Towards the Development of Anti-Inflammatory Inhibitors of IKKβ

Bamborough

Callahan²,

Christopher³

et al. 2009

CTMC

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The IkappaB kinases (IKKs) are essential components of the signaling pathway by which the NF-kappaB p50/RelA transcription factor is activated in response to pro-inflammatory stimuli such as lipopolysaccharide (LPS) and tumor necrosis factor (TNFalpha). NF-kappaB signaling results in the expression of numerous genes involved in innate and adaptive immune responses. The pathway is also implicated in chronic inflammatory disorders including rheumatoid arthritis (RA), chronic obstructive pulmonary disorder (COPD), and asthma. Inhibition of the kinase activity of the IKKs is therefore a promising mechanism for intervention in these diseases. Here, we will review the literature describing small molecule inhibitors of IKKbeta (IKK2), the most widely studied of the IKKs.

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“…[1][2][3] Certain isoquinoline alkaloids can inhibit a number of cancer-related enzymes, including inosine 5 0 -monophosphate dehydrogenase, 4 Pfmrk, 5 P-glycoprotein, 6 kinase B/Akt, 7 cyclin dependent kinase 4, 8 topoisomerase I, 9 TRPV1, 10 IkB kinase-b, 11 caspase-3, 12 and mammalian sterile 20 kinase. 13 Isoquinolines alkaloids have attracted considerable attention for use as antitumor agents, since the isolation of naphthyridinomycin in 1974.…”

Section: Introductionmentioning

confidence: 99%