The discovery of carboline analogs as potent MAPKAP-K2 inhibitors

Wu, Jiang‐Ping; Wang, Ji; Abeywardane, Asitha; Andersen, Denise L.; Emmanuel, Michel J.; Gautschi, Elda; Goldberg, Daniel R.; Kashem, Mohammed A.; Lukas, Susan; Mao, Wang; Martin, Leigh R.; Morwick, Tina M.; Moss, Neil; Pargellis, Christopher A.; Patel, Usha; Patnaude, Lori; Peet, Gregory W.; Skow, Donna; Snow, Roger J.; Ward, Yancey D.; Werneburg, Brian; White, André

doi:10.1016/j.bmcl.2007.05.101

Cited by 58 publications

(36 citation statements)

References 10 publications

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“…MK2 is a downstream kinase of p38 MAPK that is directly phosphorylated by p38 MAPK and that has also attracted attention as a target for anti-inflammatory therapy (Gaestel et al, 2007;Ronkina et al, 2010). In fact, several groups have developed programs for anti-inflammatory therapies by generating MK2 inhibitors and have reported crystal structures of MK2 (Wu et al, 2007;Hilling et al, 2007;Anderson et al, 2007;Revesz et al, 2010;Velcicky et al, 2010;Argiriadi et al, 2009Argiriadi et al, , 2010Fujino et al, 2010;Barf et al, 2011;Oubrie et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Structure of the β-form of human MK2 in complex with the non-selective kinase inhibitor TEI-L03090

et al. 2013

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PDB reference: MK2-TEI-L03090 complex, 3wi6Mitogen-activated protein kinase-activated protein kinase 2 (MK2 or MAPKAP-K2), a serine/threonine kinase from the p38 mitogen-activated protein kinase signalling pathway, plays an important role in the production of TNF-and other cytokines. In a previous report, it was shown that MK2 in complex with the selective inhibitor TEI-I01800 adopts an -helical glycine-rich loop that is induced by the stable nonplanar conformer of TEI-I01800. To understand the mechanism of the structural change, the structure of MK2 bound to TEI-L03090, which lacks the key substituent found in TEI-I01800, was determined. MK2-TEI-L03090 has a -sheet glycine-rich loop in common with other kinases, as predicted. This result suggests that a small compound can induce a drastic conformational change in the target protein structure and can be used to design potent and selective inhibitors.

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Section: Introductionmentioning

confidence: 99%

Structure of the β-form of human MK2 in complex with the non-selective kinase inhibitor TEI-L03090

et al. 2013

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“…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 .…”

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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

116

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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.

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“…Carbolines from another HTS campaign lead to the identification of thiazolamide-substituted carbolines, such as 2.24 ( Figure 2.5) [71]. Although their cellular activity is limited, due to poor cell permeability, they possess cell-free potency and selectivity [71].…”

Section: Hsp27mentioning

confidence: 98%

Targeting the Protein Quality Control (PQC) Machinery

Seneci

2015

Chemical Modulators of Protein Misfolding and Neurodegenerative Disease

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The discovery of carboline analogs as potent MAPKAP-K2 inhibitors

Cited by 58 publications

References 10 publications

Structure of the β-form of human MK2 in complex with the non-selective kinase inhibitor TEI-L03090

Structure of the β-form of human MK2 in complex with the non-selective kinase inhibitor TEI-L03090

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

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