Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes

Angell, Richard; Angell, Tony D.; Bamborough, Paul; Bamford, Mark J.; Chung, Chun‐wa; Cockerill, Stuart; Flack, Stephen S.; Jones, Katherine L.; Lainé, Dramane I.; Longstaff, Timothy; Ludbrook, Steve; Pearson, R. M.; Smith, Kathryn J.; Smee, Penny A.; Somers, Don O.; Walker, Ann L.

doi:10.1016/j.bmcl.2008.06.028

Cited by 58 publications

(48 citation statements)

References 20 publications

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“…Inhibitors that engage this DFG pocket in p38␣ exhibit significantly slower association and dissociation binding kinetics (Pargellis et al, 2002) relative to the classical ATP competitive inhibitors. Interactions with this DFG-out pocket in p38␣, although generally enhancing compound affinity, may result in decreased selectivity for kinase inhibitors (Angell et al, 2008). Interpretation of p38 kinase-driven biology by using highly selective inhibitors such as PH-797804 is more conclusive than studies using earlier generation p38 inhibitors in which significant kinase crossover was observed (Karaman et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Properties of a NovelN-Phenyl Pyridinone Inhibitor of p38 Mitogen-Activated Protein Kinase: Preclinical-to-Clinical Translation

Hope¹,

Anderson²,

Burnette³

et al. 2009

J Pharmacol Exp Ther

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Signal transduction through the p38 mitogen-activated protein (MAP) kinase pathway is central to the transcriptional and translational control of cytokine and inflammatory mediator production. p38 MAP kinase inhibition hence constitutes a promising therapeutic strategy for treatment of chronic inflammatory diseases, based upon its potential to inhibit key pathways driving the inflammatory and destructive processes in these debilitating diseases. The present study describes the pharmacological properties of the Nphenyl pyridinone p38 MAP kinase inhibitor benzamide [3-[3-bromo-4-[(2,4-PH-797804 is an ATP-competitive, readily reversible inhibitor of the ␣ isoform of human p38 MAP kinase, exhibiting a K i ϭ 5.8 nM. In human monocyte and synovial fibroblast cell systems, PH-797804 blocks inflammation-induced production of cytokines and proinflammatory mediators, such as prostaglandin E 2 , at concentrations that parallel inhibition of cell-associated p38 MAP kinase. After oral dosing, PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. Furthermore, PH-797804 demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis. Finally, PH-797804 reduced tumor necrosis factor-␣ and interleukin-6 production in clinical studies after endotoxin administration in a dose-dependent manner, paralleling inhibition of the target enzyme. Low-nanomolar biochemical enzyme inhibition potency correlated with p38 MAP kinase inhibition in human cells and in vivo studies. In addition, a direct correspondence between p38 MAP kinase inhibition and antiinflammatory activity was observed with PH-797804, thus providing confidence in dose projections for further human studies in chronic inflammatory disease.Rheumatoid arthritis (RA) is an aggressive autoimmune disease involving complex interactions among T cells, macrophages, synoviocytes, and other immune cells (Firestein, 2003). Analysis of synovial fluid and tissue from RA patients implicated key cytokines, including TNF-␣, IL-1␤, and IL-6 in the pathogenesis of the disease (Firestein et al., 1990). Further studies shed light on the complex networks within which these cytokines function and the delicate balance between a pro-or an anti-inflammatory outcome (McInnes and ABBREVIATIONS: RA, rheumatoid arthritis; TNF, tumor necrosis factor; IL, interleukin; COX, cyclooxygenase; MAP, mitogen-activated protein; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH 2 -terminal kinase; benzamide,methoxy]-6-methyl-2-oxo-1(2H)-pyridinyl]-N,4-dimethyl-, (Ϫ)-(9CI); SCW, streptococcal cell wall; LPS, lipopolysaccharide; MKK, mitogen-activated protein kinase kinase; EGFRP, epidermal growth factor receptor peptide; GST, glutathione transferase; RASF, rheumatoid arthritis synovial fibroblast(s); MK-2, mitogen-activated protein kinase-act...

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Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Properties of a NovelN-Phenyl Pyridinone Inhibitor of p38 Mitogen-Activated Protein Kinase: Preclinical-to-Clinical Translation

Hope¹,

Anderson²,

Burnette³

et al. 2009

J Pharmacol Exp Ther

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“…The urea/amide moiety of the allosteric inhibitors is considered to be fundamental for the DFG flip 11 triggered by the establishment of two specific H-bonds with residues D 168 (belonging to the activation loop) and residue E 71 (belonging to Helix-C). 12,13 Whereas the hypothesis of a DFG-out conformation induced by allosteric inhibitors is generally supported by the results of X-ray experiments and by their slow binding kinetics experimentally observed, 14,12 the existence of a dynamic equilibrium between the DFG-in and DFG-out conformations of p38a in its apo and complexed form has been first advanced on the basis of the results of NMR studies. 15 The authors hypothesize that the DFG-out state is sampled less frequently than the DFG-in conformation; type-II inhibitors bind to the DFG-out form, freezing the protein in this conformation and suppressing the conformational exchange, while the binding of traditional inhibitors (ATP-site binders) affects the DFG equilibrium to a lesser extent.…”

Section: Introductionmentioning

confidence: 99%

Insights into MAPK p38α DFG flip mechanism by accelerated molecular dynamics

Filomia¹,

Rienzo²,

Menziani³

2010

Bioorganic & Medicinal Chemistry

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“…It is known that even small changes in ligand structure can often have very dramatic affects on activity confirming subtle interactions are often at play [1,2]. An ability to more effectively understand and predict these subtleties is one of the next challenges in SBD which will allow now routinely determined 3D crystallographic coordinates to be used in a more quantitative fashion to guide the structural modification of a lead series [3,4].…”

Section: Introductionmentioning

confidence: 99%