Pyrazinoindolone inhibitors of MAPKAP-K2

Goldberg, Daniel R.; Choi, Y.; Cogan, Derek A.; Corson, Melissa H.; DeLeon, Rodney P.; Gao, A.; Gruenbaum, Lore; Hao, Ming‐Hong; Joseph, David; Kashem, Mohammed A.; Miller, Clinton M.; Moss, Neil; Netherton, Matthew R.; Pargellis, Christopher A.; Pelletier, Julien; Sellati, Rosemarie; Skow, Donna; Torcellini, Carol A.; Tseng, Yin‐Chao; Wang, J.; Wasti, Ruby; Werneburg, Brian; Wu, Jiayan; Xiong, Zhaoming

doi:10.1016/j.bmcl.2007.12.037

Cited by 52 publications

(26 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Transformation of the indolopyridinone scaffold into the corresponding dihydropyrazino[1,2- a ]indolone 61 resulted in a slight improvement in cell-free assay, although cellular potency was maintained at micromolar concentrations (compare activity data for 39 and 41 , as well as and 40 and 42 ). However, the basic nitrogen atom of the piperidine analogues led to better solubility (about 100 mg/L for 42 at pH = 7.4, in comparison to cyclohexyl compounds, such as 39 and 41 , that showed a solubility lower than 1.5 mg/L).…”

Section: Crystallization Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

2015

View full text Add to dashboard Cite

The p38/MAPK-activated kinase 2 (MK2) pathway is involved in a series of pathological conditions (inflammation diseases and metastasis) and in the resistance mechanism to antitumor agents. None of the p38 inhibitors entered advanced clinical trials because of their unwanted systemic side effects. For this reason, MK2 was identified as an alternative target to block the pathway, but avoiding the side effects of p38 inhibition. However, ATP-competitive MK2 inhibitors suffered from low solubility, poor cell permeability, and scarce kinase selectivity. Fortunately, non-ATP-competitive inhibitors of MK2 have been already discovered that allowed circumventing the selectivity issue. These compounds showed the additional advantage to be effective at lower concentrations in comparison to the ATP-competitive inhibitors. Therefore, although the significant difficulties encountered during the development of these inhibitors, MK2 is still considered as an attractive target to treat inflammation and related diseases, to prevent tumor metastasis, and to increase tumor sensitivity to chemotherapeutics.

show abstract

Section: Crystallization Studiesmentioning

confidence: 99%

“…However, 47 did not affected TNFα production in the LPS assay, probably because of its high binding to plasma proteins. 61 …”

Section: Crystallization Studiesmentioning

confidence: 99%

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

2015

View full text Add to dashboard Cite

show abstract

“…Having a potent and selective MK2 kinase inhibitor as an investigative tool, however, would be advantageous for further exploring the biology of MK2 and the p38 kinase pathway. Potent MK2 inhibitors have been recently described (Anderson et al, 2005(Anderson et al, , 2009aTrujillo et al, 2007;Wu et al, 2007;Goldberg et al, 2008;Schlapbach et al, 2008;Xiong et al, 2008;Keminer et al, 2009), but few show nanomolar potency in cells (Schlapbach et al, 2008;Anderson et al, 2009b). Developing potent, selective MK2 inhibitors that have optimized pharmacologic properties for activity in blood or in vivo has been extremely difficult, with just one compound from the pyrrolopyridine series reported to have oral efficacy in blocking TNF␣ production in LPS-challenged rats .…”

mentioning

confidence: 99%

A Benzothiophene Inhibitor of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Inhibits Tumor Necrosis Factor α Production and Has Oral Anti-Inflammatory Efficacy in Acute and Chronic Models of Inflammation

Mourey

Burnette²,

Brustkern³

et al. 2010

J Pharmacol Exp Ther

111

View full text Add to dashboard Cite

Activation of the p38 kinase pathway in immune cells leads to the transcriptional and translational regulation of proinflammatory cytokines. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), a direct downstream substrate of p38 kinase, regulates lipopolysaccharide (LPS)-stimulated tumor necrosis factor ␣ (TNF␣) and interleukin-6 (IL-6) production through modulating the stability and translation of these mRNAs. Developing small-molecule inhibitors of MK2 may yield anti-inflammatory efficacy with a different safety profile relative to p38 kinase inhibitors. This article describes the pharmacologic properties of a benzothiophene MK2 inhibitor, PF-3644022 [(10R)-10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5Ј,6Ј:4,5]thieno[3,2-f]quinolin-8-one]. PF-3644022 is a potent freely reversible ATP-competitive compound that inhibits MK2 activity (K i ϭ 3 nM) with good selectivity when profiled against 200 human kinases. In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNF␣ production with similar activity (IC 50 ϭ 160 nM). PF-3644022 blocks TNF␣ and IL-6 production in LPS-stimulated human whole blood with IC 50 values of 1.6 and 10.3 M, respectively. Inhibition of TNF␣ in U937 cells and blood correlates closely with inhibition of phospho-heat shock protein 27, a target biomarker of MK2 activity. PF-3644022 displays good pharmacokinetic parameters in rats and is orally efficacious in both the rat acute LPS-induced TNF␣ model and the chronic streptococcal cell wall-induced arthritis model. Dose-dependent inhibition of TNF␣ production in the acute model and inhibition of paw swelling in the chronic model is observed with ED 50 values of 6.9 and 20 mg/kg, respectively. PF-3644022 efficacy in the chronic inflammation model is strongly correlated with maintaining a C min higher than the EC 50 measured in the rat LPS-induced TNF␣ model.

show abstract

“…Although their cellular activity is limited, due to poor cell permeability, they possess cell-free potency and selectivity [71]. An improvement in terms of cellular potency, solubility, lipophilicity, and in vivo PK profile is provided by piperidine-containing spiroderivatives such as 2.25 [72], which do not show efficacy in a mouse model of LPS-stimulated TNFa production.…”

Section: Hsp27mentioning

confidence: 98%

Targeting the Protein Quality Control (PQC) Machinery

Seneci

2015

Chemical Modulators of Protein Misfolding and Neurodegenerative Disease

View full text Add to dashboard Cite

Pyrazinoindolone inhibitors of MAPKAP-K2

Cited by 52 publications

References 15 publications

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

A Benzothiophene Inhibitor of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Inhibits Tumor Necrosis Factor α Production and Has Oral Anti-Inflammatory Efficacy in Acute and Chronic Models of Inflammation

Targeting the Protein Quality Control (PQC) Machinery

Contact Info

Product

Resources

About