The as-yet unfulfilled promise of p38 MAPK inhibitors

Sweeney, Susan E.

doi:10.1038/nrrheum.2009.171

Cited by 37 publications

(30 citation statements)

References 9 publications

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“…For example, whereas a systematic approach to determining the mechanism(s) underlying SAP/MAPK and JAK/STAT inhibition by SMIs and suppression of synoviocyte-, chondrocyte-and osteoclast-mediated pathophysiologic biomarkers have been performed [33-37, 46, 49, 57, 58, 71, 72], similar study design in animal models of arthritis [58,64,72] have then assessed the effect of p38 kinase inhibition on amelioration of arthritis severity with encouraging results [65,78]. However, the results from several human RA clinical trials involving p38 kinase inhibition have been generally discouraging [79][80][81][82]. One interpretation of these results from human RA clinical trials is that p38 kinase SMIs can only transiently alter RA pathophysiology.…”

Section: The 'Cross-talk' Patterns That Exist Between Multiple Kinasementioning

confidence: 96%

Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways

Malemud¹

2011

aiaaamc

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A skewed repertoire of pro-inflammatory cytokines produced by the T h 1 subset, one of the hallmarks of rheumatoid arthritis (RA), is characterized by an overabundance of pro-inflammatory cytokines. Tumor necrosis factor-, interleukin-1 (IL-1), IL-6, IL-7, IL-8, IL-21, IL-12/IL-23, IL-15, IL-17, IL-18, IL-32, and interferon-are primarily responsible for immune-mediated inflammation of RA by activating Janus kinases (JAK) -1, -2, -3, p38 kinase, C-Jun-Nterminal kinase, extracellular signal-regulated kinase 1/2 and the phosphatidylinosotide-3-kinase/Akt/mTor pathways. Activation of these signaling pathways results in up-regulation of pro-inflammatory cytokines, cyclooxygenase-2, matrix metalloproteinases, pro-angiogenesis proteins and anti-apoptosis proteins, the latter resulting in abnormal survival of activated T-and B-cells. Further, IL-17 also regulates the differentiation of CD4 + T-helper cells by inducing a T h 17 T-cell subset, and a subpopulation of T-regulatory (T reg ) cells. Although T reg cells are sufficiently abundant in RA synovial fluid, they fail to induce immune tolerance suggesting a functional deficiency likely coupled to putative protein kinase signaling abnormalities. The results of in vitro and studies in animal models of arthritis have indicated that inhibiting individual signaling pathways can blunt the synthesis of several of the pro-inflammatory biomarkers characteristic of human RA pathology. However, RA clinical trials indicated that small molecule inhibitors of JAK-1, -2-, 3 and/or p38 kinase while exhibiting acceptable safety and tolerability profiles have only marginal and transient clinical effectiveness. These results suggested that future RA clinical studies using these or other kinase inhibitors will have to consider strategies designed to simultaneously inhibit multiple kinase pathways.

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Section: The 'Cross-talk' Patterns That Exist Between Multiple Kinasementioning

confidence: 96%

Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways

Malemud¹

2011

aiaaamc

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“…However, most of the outcomes of using the p38 inhibitors in clinical trials have been disappointing as a result of adverse events stemming from drug toxicity [81]. Although many studies of the p38 inhibitor in myocardial ischemia seem to support the benefit of the p38 inhibitor in reducing myocardial injury and improving cardiac function, the majority of clinical trials with p38 inhibitors have been mainly aimed at studying its antiinflammatory effect, not for myocardial infarctions.…”

Section: Reports Of P38 Inhibitors In An In Vivo Model Of Ischemia/rementioning

confidence: 98%

Role of p38 inhibition in cardiac ischemia/reperfusion injury

Kumphune

Chattipakorn

2011

Eur J Clin Pharmacol

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The p38 mitogen-activated protein kinases (p38s) are Ser/Thr kinases that are activated as a result of cellular stresses and various pathological conditions, including myocardial ischemia/reperfusion. p38 activation has been shown to accentuate myocardial injury and impair cardiac function. Inhibition of p38 activation and its activity has been proposed to be cardioprotective by slowing the rate of myocardial damage and improving cardiac function. The growing body of evidence on the use of p38 inhibitors as therapeutic means for responding to heart problems is controversial, since both beneficial as well as a lack of protective effects on the heart have been reported. In this review, the outcomes from studies investigating the effect of p38 inhibitors on the heart in a wide range of study models, including in vitro, ex vivo, and in vivo models, are discussed. The correlations of experimental models with practical clinical usefulness, as well as the need for future studies regarding the use of p38 inhibitors, are also addressed.

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“…Moreover, various disorders were connected with p38 MAPK signalling pathway such as artheriosclerosis [6,7] (via increased production of proinflammatory cytokines induced by oxidized low-density lipoprotein in human mast cell line and by inhibition of the formation of human macrophage-derived foam cells), platelet activation and thrombus formation [8] (through abrogation of p38 MAPKdependent phosphorylation of platelet cytosolic phospholipase A2), diabetic peripheral neuropathy [9] (by activated CD8(+)-T-cells mediating cytotoxicity toward Schwann cells), periodontal disease [10] (via modulation of CC chemokine ligand 11 (CCL11) related Th2 cells migration in human gingival fibroblasts), inflammation in human pulmonary epithelial cells [11] (through TNF-α triggered chemokine CXCL1 release) and induced proinflammatory cytokines production in macrophages [12] (via IL-17A). However, up to now, several generations of p38 MAP kinase inhibitors failed in clinical trials predominantly due to lack of efficacy and/or a poor safety profile [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

Fehr

Unger²,

Schaeffeler

et al. 2015

Cell Physiol Biochem

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Background/Aims: Inhibition of p38 mitogen-activated protein kinase (p38 MAPK) is promising for the treatment of inflammatory disorders, however, the efficacy of p38 MAPK inhibitors in clinical trials is limited so far. Since functional sensitivity of p38 MAPK is commonly predicted by preclinical species, we systematically investigated interspecies differences including human tissue. Methods: Ex vivo test models were established using whole blood and primary cells from different species such as mice, rats, pigs and humans to compare LPS-induced TNF-α inhibition of four different p38 MAPK reference inhibitors SB 203580, BIRB-796, Pamapimod, and a Losmapimod analogue as well as a proprietary imidazole-based p38 MAPK Inhibitor. Results: All analysed p38 MAPK inhibitors resulted in significant inhibition of LPS-induced TNF-α release but with high interspecies differences for dose sensitivity. IC₅₀ values from human whole blood and PBMC showed significant higher sensitivity towards p38 MAPK inhibition compared with data from pig and rat. Conclusion: Inhibition of TNF-α release by p38 MAPK inhibitors can be reliably identified in well-established laboratory species such as rat or mouse. However, our data indicate that animal models appear to be limited for valid prediction of the inhibitory potential for TNF-α release in humans. Thus, human tissues should be considered early in the drug development process of p38 MAPK inhibitors.

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The as-yet unfulfilled promise of p38 MAPK inhibitors

Cited by 37 publications

References 9 publications

Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways

Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways

Role of p38 inhibition in cardiac ischemia/reperfusion injury

Impact of p38 MAP Kinase Inhibitors on LPS-Induced Release of TNF-α in Whole Blood and Primary Cells from Different Species

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