Pharmacological profile of AW-814141, a novel, potent, selective and orally active inhibitor of p38 MAP kinase

Chopra, Puneet; Kulkarni, Onkar P.; Gupta, Shashank; Bajpai, Malini; Kanoje, Vijay; Banerjee, Manish; Bansal, Vimal; Visaga, Senthil; Chatterjee, Mou; Chaira, Tridib; Shirumalla, Raj Kumar; Verma, A. K.; Dastidar, Sunanda G.; Sharma, Geeta; Ray, Abhijit

doi:10.1016/j.intimp.2010.01.007

Cited by 8 publications

(6 citation statements)

References 29 publications

(29 reference statements)

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“…It was thus seen that binding affinity directly correlated with inhibitory activity. It was also seen from the IC 50 values that peptide VWCS is a better inhibitor of p38β than the known inhibitors (23–28). This inhibition was shown in the presence of substrate of p38β, which proves that VWCS is the potent and competitive inhibitor.…”

Section: Discussionmentioning

confidence: 85%

“…The activity assay was performed in 96-well microtiter plate coated with ATF2 protein and incubated at 37°C. Of p38b protein, 12 lg was incubated with seven different concentrations of the peptide (15,20,25,30,35,40, and 45 nM) for 1.5 h, and then 100 lM of ATP was added to the reaction mixture (200 lL). All assays were performed in three replicates for each concentration, and means € SD values were used to calculate the IC 50 value.…”

Section: Analytical Rp-hplc Of Peptidesmentioning

confidence: 99%

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p38β MAP Kinase as a Therapeutic Target for Pancreatic Cancer

et al. 2012

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† First authors (both have equal contribution).Pancreatic cancer is very difficult to diagnose in its early stage. Molecular marker and imaging have not proven to be accurate modalities for screening of pancreatic cancer. This study aims to develop p38b as a protein marker for pancreatic cancer and to design peptide inhibitor against the same. The serum p38b level of pancreatic cancer (n = 35; 5.06 lg ⁄ mL) was twofold higher compared to that of the chronic pancreatitis (n = 10; 2.92 lg ⁄ mL) and matched normal control (n = 10; 2.86 lg ⁄ ml) (p < 0.0005). Peptide inhibitors were designed to inhibit the activity of p38b and the kinetic assay had shown the dissociation constant, (K D ) to be 3.16 · 10 )8 M and IC 50 , 25 nM by Surface Plasmon Resonance (SPR) and EnzymeLinked Immunosorbent Assay (ELISA), respectively. The peptide inhibitor also significantly reduced viability and induced cytotoxicity in Human Pancreatic carcinoma epithelial-like cell line (PANC-1) cells.

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Section: Discussionmentioning

confidence: 85%

Section: Analytical Rp-hplc Of Peptidesmentioning

confidence: 99%

p38β MAP Kinase as a Therapeutic Target for Pancreatic Cancer

et al. 2012

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“…When required, inhibitors were administered by i.p. injection at 15 mg/kg as previously reported (50,51). For in vivo neutrophil depletion, 300 μg/mouse of anti-Gr1 or the same volume of saline were i.v.…”

Section: Methodsmentioning

confidence: 99%

Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis

González‐Terán

Cortés²,

Manieri³

et al. 2012

J. Clin. Invest.

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Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-α. TNF-α is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-α expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38γ/δ MAPK proteins is required for the elongation of nascent TNF-α protein in macrophages. The MKK3/6-p38γ/δ pathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-α elongation. These results identify a new signaling pathway that regulates TNF-α production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-α production is involved.

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“…Most of these protein kinase inhibitors interfere with phosphorylation or bind in the ATP binding site. Several compounds such as SD-282, SC-409, SB (SmithKline Beecham) -242235, AW-814141 and other capable of inhibit p38 have been studied in murine models of rheumatoid arthritis and/or periodontal disease and have prevented progression of the disease and bone resorption 4,12,49,51,69 . The promising results obtained in both in vitro and in preclinical studies generated interest of pharmaceutical companies to develop protein kinase inhibitors.…”

Section: - Cell Signalin G Pathways In Periodontal Diseasementioning

confidence: 99%

Modulation of host cell signaling pathways as a therapeutic approach in periodontal disease

et al. 2012

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Recently, new treatment approaches have been developed to target the host component of periodontal disease. This review aims at providing updated information on host-modulating therapies, focusing on treatment strategies for inhibiting signal transduction pathways involved in inflammation. Pharmacological inhibitors of MAPK, NFκB and JAK/STAT pathways are being developed to manage rheumatoid arthritis, periodontal disease and other inflammatory diseases. Through these agents, inflammatory mediators can be inhibited at cell signaling level, interfering on transcription factors activation and inflammatory gene expression. Although these drugs offer great potential to modulate host response, their main limitations are lack of specificity and developments of side effects. After overcoming these limitations, adjunctive host modulating drugs will provide new therapeutic strategies for periodontal treatment.

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Pharmacological profile of AW-814141, a novel, potent, selective and orally active inhibitor of p38 MAP kinase

Cited by 8 publications

References 29 publications

p38β MAP Kinase as a Therapeutic Target for Pancreatic Cancer

p38β MAP Kinase as a Therapeutic Target for Pancreatic Cancer

Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis

Modulation of host cell signaling pathways as a therapeutic approach in periodontal disease

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