Structure–Activity Relationship Studies of Ethyl 2-[(3-Methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate: An Inhibitor of AP-1 and NF-κB Mediated Gene Expression

Palanki, Moorthy S. S.; Gayo‐Fung, Leah M.; Shevlin, Graziella; Erdman, Paul; Sato, Mark; Goldman, Mark E.; Ransone, Lynn J.; Spooner, Cheryl

doi:10.1016/s0960-894x(02)00517-6

Cited by 43 publications

(13 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both hits 29 (117) and 39 (116) were found to inhibit AP-1 and NF-κB mediated transcriptional activation without blocking basal transcription driven by the β-actin promoter and to exhibit a similar inhibitory effect on the production of IL-2 and IL-8 levels in stimulated Jurkat T-cells.…”

Section: Development Of Small Molecules Targeting Ap-1mentioning

confidence: 97%

“…By screening their diversified compound library using automated high-throughput assays with stably transfected human Jurkat T-cells, Palanki and colleagues 116,117 have also identified another two novel hits, 29 and its isomer 39 (Figures 6 and 7), which display a slightly lower potency than their earlier hit 2 (IC 50 of 2.0 and 1.0 vs 0.5 μM, respectively). Both hits 29 (117) and 39 (116) were found to inhibit AP-1 and NF-κB mediated transcriptional activation without blocking basal transcription driven by the β-actin promoter and to exhibit a similar inhibitory effect on the production of IL-2 and IL-8 levels in stimulated Jurkat T-cells.…”

Section: Development Of Small Molecules Targeting Ap-1mentioning

confidence: 99%

See 1 more Smart Citation

Small Molecule Inhibitors Targeting Activator Protein 1 (AP-1)

et al. 2014

View full text Add to dashboard Cite

Activator protein 1 (AP-1) is a pivotal transcription factor that regulates a wide range of cellular processes including proliferation, apoptosis, differentiation, survival, cell migration, and transformation. Accumulating evidence supports that AP-1 plays an important role in several severe disorders including cancer, fibrosis, and organ injury, as well as inflammatory disorders such as asthma, psoriasis, and rheumatoid arthritis. AP-1 has emerged as an actively pursued drug discovery target over the past decade. Excitingly, a selective AP-1 inhibitor T-5224 (51) has been investigated in phase II human clinical trials. Nevertheless, no effective AP-1 inhibitors have yet been approved for clinical use. Despite significant advances achieved in understanding AP-1 biology and function, as well as the identification of small molecules modulating AP-1 associated signaling pathways, medicinal chemistry efforts remain an urgent need to yield selective and efficacious AP-1 inhibitors as a viable therapeutic strategy for human diseases.

show abstract

Section: Development Of Small Molecules Targeting Ap-1mentioning

confidence: 97%

Section: Development Of Small Molecules Targeting Ap-1mentioning

confidence: 99%

Small Molecule Inhibitors Targeting Activator Protein 1 (AP-1)

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Although most IKK- β inhibitors reported so far are still in preclinical stages of development, a number of novel small-molecule inhibitors of IKK- β have been described. For example, SPC-839, a member of a series of quinazoline analogues developed by Celgene [297-299], is one of the more extensively studied IKK- β inhibitors. SPC-839 inhibits IKK- β with an IC50 of 62 nM, and has a 200-fold selectivity for IKK- β over IKK- α (IC50 = 13 μ M).…”

Section: Small Molecule Nf- κB Inhibitors As Chemopreventive Agentsmentioning

confidence: 99%

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

et al. 2014

View full text Add to dashboard Cite

Activation of nuclear factor-kappa B (NF- κB) as a mechanism of host defense against infection and stress is the central mediator of inflammatory responses. A normal (acute) inflammatory response is activated on urgent basis and is auto-regulated. Chronic inflammation that results due to failure in the regulatory mechanism, however, is largely considered as a critical determinant in the initiation and progression of various forms of cancer. Mechanistically, NF- κB favors this process by inducing various genes responsible for cell survival, proliferation, migration, invasion while at the same time antagonizing growth regulators including tumor suppressor p53. It has been shown by various independent investigations that a down regulation of NF- κB activity directly, or indirectly through the activation of the p53 pathway reduces tumor growth substantially. Therefore, there is a huge effort driven by many laboratories to understand the NF- κB signaling pathways to intervene the function of this crucial player in inflammation and tumorigenesis in order to find an effective inhibitor directly, or through the p53 tumor suppressor. We discuss here on the role of NF- κB in chronic inflammation and cancer, highlighting mutual antagonism between NF- κB and p53 pathways in the process. We also discuss prospective pharmacological modulators of these two pathways, including those that were already tested to affect this mutual antagonism.

show abstract

“…Quinazoline analogues have been extensively studied for selective IKKβ inhibition, one of most potent compounds in this series SPC-839 with IC 50 60 nM having more than 200 times selectivity for IKKβ [236].…”

Section: Nfκb and Ikkβ Inhibitorsmentioning

confidence: 99%

Novel Targets for Antiinflammatory and Antiarthritic Agents

Kulkarni

Achaiah²,

Sastry³

2006

CPD

View full text Add to dashboard Cite

Inflammation is a complex pathological condition associated with exaggerated human immune system involving various activated immune cells and bio-molecules. Treatment of inflammatory diseases particularly chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease etc. has been a big challenge for scientists as there are no safe drugs available for cure. Current therapeutic approaches to the treatment of inflammatory diseases are centered on cycloxygenase (both COX-1 and 2) proinflammatory enzymes but present available drugs of this category are associated with undesirable gastrointestinal and cardiovascular side effects. Recent scientific advents draw out the secrets of inflammation cache and understanding the involvement of several factors acting as stimulators or inhibitors thus opening new avenues for drug discoveries. Several bio-molecules such as proinflammatory cytokines, components of signal transduction and matrix degrading enzymes resolve inflammatory responses, might be new targets for treatment of chronic inflammatory diseases. This review gathers recent advances in drug research focusing interleukin-1, TNF-alpha, p38 kinase, c-Jun N-terminal kinase MAP kinase, NFkappaB, and matrix metalloproteinases. The biological roles of these inflammatory mediators are clearly understood thus offering new targets for design of novel inhibitors for incurable inflammatory diseases. This also provides an overview of the current nonsteroidal antiinflammatory agents.

show abstract

Structure–Activity Relationship Studies of Ethyl 2-[(3-Methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate: An Inhibitor of AP-1 and NF-κB Mediated Gene Expression

Cited by 43 publications

References 14 publications

Small Molecule Inhibitors Targeting Activator Protein 1 (AP-1)

Small Molecule Inhibitors Targeting Activator Protein 1 (AP-1)

Chronic inflammation and cancer: potential chemoprevention through nuclear factor kappa B and p53 mutual antagonism

Novel Targets for Antiinflammatory and Antiarthritic Agents

Contact Info

Product

Resources

About