p38 MAPK - SPR BINDING ASSAY

Our service for comprehensive kinetic characterization of your small molecule kinase inhibitors

Theoretical background: The p38 MAPK (mitogen-activated protein kinase) pathway contains protein kinases which engage in respond to various extracellular stimuli an intracellular signalling cascade, coordinating the activation of gene transcription, protein synthesis, cell cycle machinery, cell death, and differentiation. The different p38 MAPK family members (p38α, p38β, p38γ, p38δ) encoded by different genes are approximately 60% identical in their amino acid sequence but have different tissue expression patterns. p38 MAPKs are activated by dual phosphorylation by upstream kinases (MKK6 and MKK3). Upon activation p38 MAP kinases can phosphorylate substrates such as transcription factors thus directly regulating gene expression and transcriptional activity. Because of the important role of p38α in inflammatory diseases it is an interesting pharmaceutical target. 

 

p38 MAPK and inhibitors: p38 MAPKs are selectively inhibited by pyridinylimidazole compounds e.g. SB203580 (p38α: KD = 17 nM, p38β: KD = 250 nM [1]), its analogues PD169316 and SB202190 which bind the active as well as the inactive forms with equal affinity. SB203580 selectively binds α- and β-isoforms but is not effective for p38γ and p38δ. BIRB 796, a diaryl urea compound, interacts with p38 MAPKs by a novel mechanism, indirectly competing with the binding of ATP (p38α KI = 2 nM [1]) and is a potential agent for the treatment of inflammatory diseases. VX-745, an ATP-competitive inhibitor, is active against the α-, β- and γ-isotypes and is still in clincical trials [2].

Figure: Real-time kinetic analysis of kinase inhibitor SB203580 binding to p38α (figure above) and p38β (figure below) using surface plasmon resonance.

 

[1] Yong et al. (2009) Expert Opin Investig Drugs. 18(12):1893-905.
[2] Goldstein et al (2010) J.Med.Chem.53(6):2345-53.

 

We provide our Kinascreen services to kinetically characterize small molecule kinase inhibitors for all p38 isoforms (p38α, p38β, p38γ and p38δ) in their phosphorylated (activated) and unphosphorylated (non-activated) state.

 

Please contact our application specialists to obtain more information and an individual quote tailored to your specific needs.

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