Discovery of novel and selective IKK-β serine-threonine protein kinase inhibitors. Part 1

Murata, Toshiki; Shimada, Mitsuyuki; Sakakibara, Satoshi; Yoshino, T.; Kadono, Hiroshi; Masuda, Tsutomu; Shimazaki, Makoto; Shintani, Takuya; Fuchikami, Kinji; Sakai, Katsuya; Inbe, Hisayo; Takeshita, Kenjiro; Niki, Toshiro; Umeda, Masaomi; Bacon, Kevin B.; Ziegelbauer, Karl; Lowinger, Timothy B.

doi:10.1016/s0960-894x(02)01046-6

Cited by 175 publications

(59 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4) to be a moderately potent IKK inhibitor that was found to block 33 P phosphate incorporation into a biotinylated I B substrate with an IC 50 of 1.5 M. Compound 17 was selective over IKK (IC 50 >20 M) and blocked NF-B-dependent expression of several reporter genes in cellular assays, e.g. TNFinduced RANTES production in A549 cells (IC 50 = 8 M) [82].…”

Section: -Amino-6-(2-hydroxyphenyl)-pyridines -Pyrazinones and -Pyrmentioning

confidence: 99%

Progress Towards the Development of Anti-Inflammatory Inhibitors of IKKβ

Bamborough

Callahan²,

Christopher³

et al. 2009

CTMC

View full text Add to dashboard Cite

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.

show abstract

Section: -Amino-6-(2-hydroxyphenyl)-pyridines -Pyrazinones and -Pyrmentioning

confidence: 99%

Progress Towards the Development of Anti-Inflammatory Inhibitors of IKKβ

Bamborough

Callahan²,

Christopher³

et al. 2009

CTMC

View full text Add to dashboard Cite

show abstract

“…This molecule has also inhibited LPSstimulated synthesis of proinflammatory cytokines including TNF-α, IL-1β, IL-6 and IL-8 [237]. Diaryl pyridines have been reported to possess more selectivity for IKKβ inhibition, a most potent molecule in this series exhibited in vitro inhibition of LPS induced TNF-α formation with IC 50 value 0.6 µM and in vivo inhibition with ED 50 2mg/kg body weight [238,239]. Several new leads have been reported in literature containing heterocyclic ring systems with more selectivity towards IKKβ viz thiophenes, benzimidazoles, indoles, indazoles etc.…”

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

“…Compound 25 was identified via HTS as a lead structure for IKK-2 inhibition, with an IC 50 value of 1.5 µM in a biochemical assay, and good selectivity versus IKK-1 as well as other non-related kinases [23]. This compound also shows low micromolar activity in a number of cellular assays of cytokine release, but suffers from poor oral bioavailability.…”

Section: Pyridines and Related Compoundsmentioning

confidence: 99%

Small molecule inhibitors of IKK kinase activity

Coish

Wickens

Lowinger

2005

Expert Opinion on Therapeutic Patents

View full text Add to dashboard Cite

The nuclear transcription factor NF-κB plays a significant role in the pathogenesis of a variety of diseases. Because of the key role played by the inhibitor of κB kinase (IKK) complex in the activation of NF-κB, coupled with the druggability of kinases as a target class, numerous companies have been pursuing discovery programmes aimed at identifying small molecule inhibitors of these enzymes. This paper reviews the patenting activity associated with these efforts.

show abstract

Discovery of novel and selective IKK-β serine-threonine protein kinase inhibitors. Part 1

Cited by 175 publications

References 16 publications

Progress Towards the Development of Anti-Inflammatory Inhibitors of IKKβ

Progress Towards the Development of Anti-Inflammatory Inhibitors of IKKβ

Novel Targets for Antiinflammatory and Antiarthritic Agents

Small molecule inhibitors of IKK kinase activity

Contact Info

Product

Resources

About

Discovery of novel and selective IKK-β serine-threonine protein kinase inhibitors. Part 1

Cited by 175 publications

References 16 publications

Progress Towards the Development of Anti-Inflammatory Inhibitors of IKK&#946;

Progress Towards the Development of Anti-Inflammatory Inhibitors of IKK&#946;

Novel Targets for Antiinflammatory and Antiarthritic Agents

Small molecule inhibitors of IKK kinase activity

Contact Info

Product

Resources

About

Progress Towards the Development of Anti-Inflammatory Inhibitors of IKKβ

Progress Towards the Development of Anti-Inflammatory Inhibitors of IKKβ