Aminocyanopyridine Inhibitors of Mitogen Activated Protein Kinase‐Activated Protein Kinase 2 (MK‐2).

Anderson, David R.; Hegde, Shridhar G.; Reinhard, Emily J.; Gomez, Leslie; Vernier, William F.; Lee, Len; Liu, Shuang; Sambandam, Aruna; ., Snider, Patricia, R.; Masih, Liaqat

doi:10.1002/chin.200529158

Cited by 22 publications

(32 citation statements)

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“…Furthermore, MK2-mediated phosphorylation of TRIM28 at S473 was efficiently inhibited in the presence of a commercially available selective inhibitor of MK2, MK2 inhibitor III, and rottlerin (Fig. 4D) but not the relatively poor MK2 inhibitor compound 1 (50). Further evidence for the role of MK2-mediated phosphorylation of TRIM28 was demonstrated by analysis of the phosphorylation state of TRIM28 at S473 in mouse embryonic fibroblasts (MEFs) lacking MK2 and MK3 (MK2 homologue) (Fig.…”

Section: Kshv Infection Of Primary Ecs Activates Stat3mentioning

confidence: 95%

Kaposi's Sarcoma-Associated Herpesvirus Kaposin B Induces Unique Monophosphorylation of STAT3 at Serine 727 and MK2-Mediated Inactivation of the STAT3 Transcriptional Repressor TRIM28

King

2013

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), and the inflammation-driven neoplasm Kaposi's sarcoma (KS). A triad of processes, including abnormal proliferation of endothelial cells, aberrant angiogenesis, and chronic inflammation, characterize KS lesions. STAT3 is a key transcription factor governing these processes, and deregulation of STAT3 activity is linked to a wide range of cancers, including PEL and KS. Using primary human endothelial cells (ECs), I demonstrate that KSHV infection modulated STAT3 activation in two ways: (i) KSHV induced uncoupling of canonical tyrosine (Y) and serine (S) phosphorylation events while (ii) concomitantly inducing the phosphorylation and inactivation of TRIM28 (also known as KAP-1 or TIF-1␤), a newly identified negative regulator of STAT3 activity. KSHV infection of primary ECs induced chronic STAT3 activation characterized by a shift from the canonical dual P-STAT3 Y705 S727 form to a mono P-STAT3 S727 form. Expression of the latent protein kaposin B promoted the unique phosphorylation of STAT3 at S727, in the absence of Y705, activated the host kinase mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 (MK2), and stimulated increased expression of STAT3-dependent genes, including CCL5, in ECs. TRIM28-mediated repression of STAT3 is relieved by phosphorylation of S473, and in vitro kinase assays identified TRIM28 S473 as a bona fide target of MK2. Together, these data suggest that kaposin B significantly contributes to the chronic inflammatory environment that is a hallmark of KS by unique activation of the proto-oncogene STAT3, coupled with MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28.

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Section: Kshv Infection Of Primary Ecs Activates Stat3mentioning

confidence: 95%

Kaposi's Sarcoma-Associated Herpesvirus Kaposin B Induces Unique Monophosphorylation of STAT3 at Serine 727 and MK2-Mediated Inactivation of the STAT3 Transcriptional Repressor TRIM28

King

2013

J Virol

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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

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113

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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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“…One such significant scaffold is the pyran nucleus which is the key constituent of a wide range of both natural and synthetic bioactive compounds. The compounds containing 4H-chromene scaffold have found other applications such as optical brighteners, [3] fluorescence markers, [4] pigments, [5] cosmetics, biodegradable agrochemicals, [6] mutagenicity, [7] sex pheromone, [8] laser dyes, [9] central nervous system activity, [10] and pH sensitive fluorescent materials for visualization of biomolecules. [11] Moreover, 7-Hydroxy-6methoxy-4H-chromene A (Fig.…”

Section: Figure 1: Pyran-based Heterocyclesmentioning

confidence: 99%

An Efficient, Green, Catalyst Free Synthesis and Crystallographic Study of Benzo-4h-Pyrans in Aqueous Medium

Silambarasan¹,

Nasser²

2019

J. Drug Delivery Ther.

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A highly efficient and environmentally benign for the synthesis a of 2-amino-7-hydroxy-4-aryl-4H-chromene-3-carbonitrile derivatives (4a-n) in good to high yields (90%-97%) by one-pot three-component Michael addition reaction of malononitrile, aromatic aldehydes and resorcinol under reflux condition was developed in aqueous medium. Single crystal X-ray studies show that 4h crystallizes in the formula C22H15Cl2N2O2, Mr=410.26, Monoclinic, Space group P2(1)/c, a=12.753(9)Å, b=6.665(4)Å, c=24.050(14) Å, β=102.95(3)A° and 4i C16H10Cl2N2O2, Mr=333.16, Triclinic, Space group P-1, a=6.271(3)Å, b=18.697(5)Å, c =13.794(7) Å, β =94.269(17)A°. The structure of the products were further confirmed by 1H NMR, 13C NMR, IR and Mass spectrum. Keywords: Benzopyrans, malononitrile, resorcinol, Michael addition, water mediated synthesis, single crystal XRD

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Aminocyanopyridine Inhibitors of Mitogen Activated Protein Kinase‐Activated Protein Kinase 2 (MK‐2).

Cited by 22 publications

References 1 publication

Kaposi's Sarcoma-Associated Herpesvirus Kaposin B Induces Unique Monophosphorylation of STAT3 at Serine 727 and MK2-Mediated Inactivation of the STAT3 Transcriptional Repressor TRIM28

Kaposi's Sarcoma-Associated Herpesvirus Kaposin B Induces Unique Monophosphorylation of STAT3 at Serine 727 and MK2-Mediated Inactivation of the STAT3 Transcriptional Repressor TRIM28

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

An Efficient, Green, Catalyst Free Synthesis and Crystallographic Study of Benzo-4h-Pyrans in Aqueous Medium

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