Selective p38α Inhibitors Clinically Evaluated for the Treatment of Chronic Inflammatory Disorders

Goldstein, David; Kuglstatter, A.; Lou, Yan; Soth, Michael

doi:10.1021/jm9012906

Cited by 165 publications

(135 citation statements)

References 42 publications

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“…Instead, most previous work has concentrated on other MAPK family members, primarily MAPK14, as contributing to inflammation in the airway and other sites (56) as well as driving mucus production (12,26). Based on these observations, drug development activity was generally directed at MAPK14, yielding inhibitors with increased kinase selectivity and antiinflammatory activity (19,57). The present results assign a new function for MAPK13 and should turn the field to a different strategy for the study of MAPK biology and blockade.…”

Section: Figurementioning

confidence: 80%

IL-13–induced airway mucus production is attenuated by MAPK13 inhibition

Alevy

Patel²,

Romero³

et al. 2012

J. Clin. Invest.

171

265

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Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13-driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.

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Section: Figurementioning

confidence: 80%

IL-13–induced airway mucus production is attenuated by MAPK13 inhibition

Alevy

Patel²,

Romero³

et al. 2012

J. Clin. Invest.

171

265

View full text Add to dashboard Cite

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“…p38 MAPK is involved in the regulation of proinflammatory cytokines such as TGF-b1 and TNF-a, and exhibits an inverse relationship with hepatocyte proliferation (Awad et al, 2000;Goldstein et al, 2010). Previous studies have demonstrated that the protective effect of HSYA against LPS-induced acute lung injury was associated with the significant inhibition of p38 MAPK phosphorylation in vitro and in vivo (Song et al, 2013;Sun et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Hydroxysafflor yellow A suppresses liver fibrosis induced by carbon tetrachloride with high-fat diet by regulating PPAR-γ/p38 MAPK signaling

Liu

Wang

Liu

et al. 2014

Pharmaceutical Biology

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Context: One approach to protect against liver fibrosis is the use of herb-derived natural compounds, such as hydroxysafflor yellow A (HSYA). The antifibrosis effect of HYSA against liver fibrosis has been investigated; however, its mechanisms have not yet been entirely revealed. Objectives: To study the protective effects of HSYA on liver fibrosis induced by carbon tetrachloride (CCl 4 ) and a high-fat diet (HFD), and to determine the mechanism of action of HSYA. Materials and methods: CCl 4 and HFD were used to mimic liver fibrosis in rats, and serum biochemical indicators were determined. The antifibrosis effects of HSYA were evaluated and its mechanisms were investigated by histopathological analysis, immunohistochemical staining, enzyme-linked immunosorbent assays, real-time-PCR, and western blotting. Results: HSYA reduced CCl 4 -and HFD-mediated liver fibrosis and ameliorated serum biochemical indicator, downregulated the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) (0.31 ± 0.03 protein, 0.59 ± 0.02 mRNA) and transformin growth factor-b1 (TGF-b1) (0.81 ± 0.02 protein, 0.58 ± 0.04 mRNA), and upregulated the expression of peroxisome proliferator-activated receptor-g (PPAR-g) (1.57 ± 0.13 protein, 2.48 ± 0.19 mRNA) and matrix metallopeptidases-2 (MMP-2) (2.31 ± 0.16 protein, 2.79 ± 0.22 mRNA) (p50.01, versus model group). These effects were significantly attenuated by PPAR-g antagonist GW9662 via blocking the phosphorylation of p38 MAPK. Discussion and conclusion: These data demonstrate a novel role for HSYA in inhibiting CCl 4 -and HFD-mediated liver fibrosis, and reveal that PPAR-g and p38 MAPK signaling play pivotal roles in the prevention of liver fibrosis induced by CCl 4 and HFD.

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“…101,102 In addition, this side-effect profile was observed despite molecules having different structural backbones and belonging to type I and type II inhibitor classes. 101,103 Furthermore, the evidence of clinical efficacy was limited, especially when the comparator was an established therapy for rheumatoid arthritis or the p38 inhibitor was administered on the background of active treatment. A recurrent theme was that inflammation, as measured by serum CRP, was initially suppressed but "escaped" after a few weeks despite continued p38 inhibitor administration.…”

Section: Martin Et Al P38 In Ischemic Heart Disease 363mentioning

confidence: 99%

“…A recurrent theme was that inflammation, as measured by serum CRP, was initially suppressed but "escaped" after a few weeks despite continued p38 inhibitor administration. [101][102][103] It is sobering to reflect that the preclinical models in rheumatoid arthritis predicted clinical efficacy, [101][102][103] and biological therapies targeting TNF, upstream of p38, do modify disease progression. Furthermore, despite the disappointment with p38 inhibitors, other orally active kinase inhibitors still hold promise for this same indication.…”

Section: Martin Et Al P38 In Ischemic Heart Disease 363mentioning

confidence: 99%