The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy

McLay, Iain M.; Halley, Frank; Souness, John E.; McKenna, Jeffrey M.; Benning, Véronique; Birrell, Mark A.; Burton, Brenda; Belvisi, Maria G.; Collis, Alan; Constan, Alex; Foster, Martyn; Hele, David J; Jayyosi, Zaid; Kelley, Michael J.; Maslen, Chris; Miller, Glen M.; Ouldelhkim, Marie-Claude; Page, Kenneth; Phipps, Simon; Pollock, Kenneth H.; Porter, Barry; Ratcliffe, Andrew J.; Redford, Elisabeth J.; Webber, S. E.; Slater, Bryan; Thybaud, Véronique; Wilsher, Nicola E.

doi:10.1016/s0968-0896(00)00331-x

Cited by 80 publications

(51 citation statements)

References 22 publications

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“…Although the relative expression of p38 MAPK isoforms in rheumatoid arthritis has not been fully explored, p38␣ and p38␦ MAPKs are known to be especially prevalent at sites of joint destruction (McLay et al, 2001). Here, we show that at day 24, an early phase of the disease, p38␣ MAPK, is in an active (phosphorylated) state in tissue from arthritic joints compared with nonarthritic tissue.…”

Section: Discussionmentioning

confidence: 69%

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

Medicherla¹,

Jing²,

Mangadu³

et al. 2006

J Pharmacol Exp Ther

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Section: Discussionmentioning

confidence: 69%

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

Medicherla¹,

Jing²,

Mangadu³

et al. 2006

J Pharmacol Exp Ther

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“…Among them, p38 is thought to be crucial because selective p38 inhibitors block joint inflammation and destruction in several animal models of arthritis (3). Of the p38 isoforms, p38␣ is particularly relevant for cytokine regulation in macrophages and is blocked by pyridinylimidazole compounds, such as SB203580, which compete for the ATP-binding pocket (20).…”

Section: Discussionmentioning

confidence: 99%

“…p38, in particular, is thought to play a role in rheumatoid arthritis (RA). It is expressed and activated in the rheumatoid synovial intimal lining (2), and p38 inhibitors are effective in rodent models of arthritis (3). Therefore, p38 could serve as a therapeutic target (4,5).…”

mentioning

confidence: 99%

Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis

Inoue

Boyle

Corr

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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p38 mitogen-activated protein kinase (MAPK) regulates cytokines in arthritis and is, in turn, regulated by MAPK kinase (MKK) 3 and MKK6. To modulate p38 function but potentially minimize toxicity, we evaluated the utility of targeting MKK3 by using MKK3 ؊/؊ mice. These studies showed that TNF-␣ increased phosphorylation of p38 in WT cultured synoviocytes but that p38 activation, IL-1␤, and IL-6 expression were markedly lower in MKK3 ؊/؊ synoviocytes. In contrast, IL-1␤ or LPS-stimulated p38 phosphorylation and IL-6 production by MKK3 ؊/؊ synoviocytes were normal. Detailed signaling studies showed that NF-B also contributes to IL-6 production and that TNF-␣-induced NF-B activation is MKK3-dependent. In contrast, LPS-mediated activation of NF-B does not require MKK3. To determine whether this dichotomy occurs in vivo, two inflammation models were studied. In K͞BxN passive arthritis, the severity of arthritis was dramatically lower in MKK3 ؊/؊ mice. Phospho-p38, phospho-MAPK activator protein kinase 2, IL-1␤, CXC ligand 1, IL-6, and matrix metalloproteinase (MMP) 3 levels in the joints of MKK3 ؊/؊ mice were significantly lower than in controls. Exogenous IL-1␤ administered during the first 4 days of the passive model restored arthritis to the same severity as in WT mice. In the second model, IL-6 production after systemic LPS administration was similar in WT and MKK3 ؊/؊ mice. Therefore, selective MKK3 deficiency can suppress inflammatory arthritis and cytokine production while Toll-like receptor 4-mediated host defense remains intact.cytokines ͉ inflammation ͉ rheumatoid arthritis ͉ fibroblast ͉ signal transduction

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“…Multiple MAPK pathways can be simultaneously activated, and their relative balance is determined by upstream kinase cascades known as MAPK kinase (MKKs) (1,2). p38 has been implicated in rheumatoid arthritis (RA) based on the observation that it is activated in the rheumatoid synovium (8) and that selective inhibitors are effective in animal models of arthritis (9). These studies suggest that p38 blockade might be effective in RA, and several compounds are currently being investigated in clinical trials (10,11).…”

Section: Regulation Of P38 Mapk By Mapk Kinases 3 and 6 Inmentioning

confidence: 99%

Regulation of p38 MAPK by MAPK Kinases 3 and 6 in Fibroblast-Like Synoviocytes

Hammaker

Boyle

Firestein

2005

The Journal of Immunology

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The p38 MAPK signal transduction pathway is a key regulator of IL-1 and TNF-α production in rheumatoid arthritis. Previous studies demonstrated that upstream MAPK kinases (MKK3 and MKK6) that regulate p38 are activated in rheumatoid arthritis synovium. However, their functional relevance in fibroblast-like synoviocytes (FLS) has not been determined. To investigate the relative contribution of MKK3 and MKK6 to p38 activation, the effect of dominant-negative (DN) MKK3 and MKK6 constructs on cultured FLS was evaluated. Cultured FLS were stimulated with medium or IL-1β, and immunoblotting was performed. In some experiments, cells were lysed and immunoprecipitated with anti-p38 Ab, followed by in vitro kinase assay with [γ-32P]ATP and GST-activating transcription factor-2 as substrate. IL-1β rapidly induced p38 phosphorylation in cells transfected with empty vector (pcDNA3.1), but was inhibited by 25% in cells expressing DN MKK3 or DN MKK6. Cotransfection with both DN plasmids decreased phospho-p38 by almost 75%. In vitro kinase assays on IL-1-stimulated FLS also showed that the combination of DN MKK3 and DN MKK6 markedly decreased kinase activity compared with empty vector or the individual DN plasmids. Furthermore, IL-1β-induced IL-8, IL-6, and matrix metalloproteinase-3 protein production was significantly inhibited in DN MKK3/DN MKK6-transfected cells. The constructs had no effect on the respective mediator mRNA levels. These data demonstrate that MKK3 and MKK6 make individual contributions to p38 activation in FLS after cytokine stimulation, but that both must be blocked for maximum inhibition.

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The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy

Cited by 80 publications

References 22 publications

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis

Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis

Regulation of p38 MAPK by MAPK Kinases 3 and 6 in Fibroblast-Like Synoviocytes

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