Synthesis and SAR studies of indole-based MK2 inhibitors

Xiong, Zhaoming; Gao, Donghong A.; Cogan, Derek A.; Goldberg, Daniel R.; Hao, Ming‐Hong; Moss, Neil; Pack, Edward J.; Pargellis, Christopher A.; Skow, Donna; Trieselmann, Thomas; Werneburg, Brian; White, André

doi:10.1016/j.bmcl.2008.01.119

Cited by 39 publications

(16 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SAR analysis of the MK2 inhibitory properties showed that the six-membered lactam ring was better for activity, as already found for pyrazinoindolone derivatives previously described. 62 Moreover, the NH lactam group was important for hydrogen bond interactions, and thus did not tolerate alkyl substituents. One of the most active compounds of this series was 67 , bearing a styryl chain already found as a profitable substituent for pyrrolopyrimidinones, 71 had a 1 and 9 nM activity in cell-free assay and as inhibition of TNFα production in hPBMC, respectively.…”

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

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%

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

“…Upon MK2-induced phosphorylation, Hsp27 undergoes a conformational change, shifting from large multimers to dimers to affect chaperone function and interactions with the actin cytoskeleton (27,28). Like p38 kinase, which is the target of several novel anti-inflammatory agents, MK2 kinase is a target of several anti-inflammatory drug discovery programs (29)(30)(31)(32)(33)(34).…”

mentioning

confidence: 99%

MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation

et al. 2013

View full text Add to dashboard Cite

Clostridium difficile infection (CDI) results in toxin-induced epithelial injury and marked intestinal inflammation. Fecal markers of intestinal inflammation correlate with CDI disease severity, but regulation of the inflammatory response is poorly understood. Previous studies demonstrated that C. difficile toxin TcdA activates p38 kinase in tissue culture cells and mouse ilium, resulting in interleukin-8 (IL-8) release. Here, we investigated the role of phosphorylated mitogen-activated protein kinase (MAPK)-activated protein kinase (MK2 kinase, pMK2), a key mediator of p38-dependent inflammation, in CDI. Exposure of cultured intestinal epithelial cells to the C. difficile toxins TcdA and TcdB resulted in p38-dependent MK2 activation. Toxininduced IL-8 and GRO␣ release required MK2 activity. We found that p38 and MK2 are activated in response to other actin-disrupting agents, suggesting that toxin-induced cytoskeleton disruption is the trigger for kinase-dependent cytokine response. Phosphorylated MK2 was detected in the intestines of C. difficile-infected hamsters and mice, demonstrating for the first time that the pathway is activated in infected animals. Furthermore, we found that elevated pMK2 correlated with the presence of toxigenic C. difficile among 100 patient stool samples submitted for C. difficile testing. In conclusion, we find that MK2 kinase is activated by TcdA and TcdB and regulates the expression of proinflammatory cytokines. Activation of p38-MK2 in infected animals and humans suggests that this pathway is a key driver of intestinal inflammation in patients with CDI.

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

113

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

Synthesis and SAR studies of indole-based MK2 inhibitors

Cited by 39 publications

References 30 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

MAPK-Activated Protein Kinase 2 Contributes to Clostridium difficile-Associated Inflammation

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

Contact Info

Product

Resources

About