Pyrrolo-pyrimidones: A novel class of MK2 inhibitors with potent cellular activity

Schlapbach, Achim; Feifel, Roland; Hawtin, Stuart R.; Heng, Richard; Koch, Guido; Möbitz, Henrik; Révész, Láśzló; Scheufler, Clemens; Velcicky, Juraj; Waelchli, Rudolf; Huppertz, Christine

doi:10.1016/j.bmcl.2008.10.039

Cited by 45 publications

(28 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Separately, the biphenyl isoxasole KRIBB3 inhibits tumour cell migration by blocking protein kinase C-dependent phosphorylation of Hsp27 (Shin et al, 2005) to induce mitotic arrest and to enhance apoptosis (Shin et al, 2008). Recently, it has been shown that pyrrolo-pyrimidones, a novel class of p38 MAPK/MAPK-activated protein kinase 2 (MK2) inhibitors, inhibit phosphorylation of Hsp-27, its downstream target (Schlapbach et al, 2008), and that inhibition of Hsp-27 phosphorylation at Ser 78 and Ser 82 by the MAPKAP kinase MK5 prevents the F-actin reorganisation that is necessary for cell migration (Kostenko et al, 2009). Not only is the MAPKAPK2/ Hsp-27 pathway a promising potential target for therapeutic intervention, but the isoflavone genistein, an oestrogen analog and candidate chemotherapeutic agent, inhibits cell migration by blocking activation of this pathway (Xu and Bergan, 2006), emphasising the validity of this proposed therapeutic approach.…”

Section: Discussionmentioning

confidence: 99%

Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement

et al. 2009

View full text Add to dashboard Cite

Background: This study was performed to test the hypothesis that expression of small heat shock protein Hsp-27 is, at diagnosis, a reliable predictive biomarker of clinically aggressive prostate cancer. Methods: A panel of tissue microarrays constructed from a well-characterised cohort of 553 men with conservatively managed prostate cancer was stained immunohistochemically to detect Hsp-27 protein. Hsp-27 expression was compared with a series of pathological and clinical parameters, including outcome. Results: Hsp-27 staining was indicative of higher Gleason score ( P <0.001). In tissue cores having a Gleason score >7, the presence of Hsp-27 retained its power to independently predict poor clinical outcome ( P <0.002). Higher levels of Hsp-27 staining were almost entirely restricted to cancers lacking ERG rearrangements ( χ 2 trend=31.4, P <0.001), although this distribution did not have prognostic significance. Interpretation: This study has confirmed that, in prostate cancers managed conservatively over a period of more than 15 years, expression of Hsp-27 is an accurate and independent predictive biomarker of aggressive disease with poor clinical outcome ( P <0.001). These findings suggest that apoptotic and cell-migration pathways modulated by Hsp-27 may contain targets susceptible to the development of biologically appropriate chemotherapeutic agents that are likely to prove effective in treating aggressive prostate cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Another approach is to impede phosphorylation of Hsp27. Numerous specific inhibitors against some of the Hsp27 kinases have been developed [173][174][175][176], but clinical trials in patients suffering from conditions with abnormal Hsp27 phosphorylation are lacking. Cell culture studies with a cell permeable MK2 inhibitor protein showed that preventing phosphorylation of Hsp27 reversed TGF-b1-induced F-actin rearrangements in human keloid fibroblasts, indicating that administration of Hsp27 kinase inhibitors may be a promising strategy in conditions with anomalous Hsp27 phosphorylation [177].…”

Section: Therapeutic Strategies Against Anomalous Hsp27 Phosphorylationmentioning

confidence: 99%

Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology

Kostenko

Moens

2009

Cell. Mol. Life Sci.

312

314

View full text Add to dashboard Cite

The small heat shock protein Hsp27 or its murine homologue Hsp25 acts as an ATP-independent chaperone in protein folding, but is also implicated in architecture of the cytoskeleton, cell migration, metabolism, cell survival, growth/differentiation, mRNA stabilization, and tumor progression. A variety of stimuli induce phosphorylation of serine residues 15, 78, and 82 in Hsp27 and serines 15 and 86 in Hsp25. This post-translational modification affects some of the cellular functions of Hsp25/27. As a consequence of the functional importance of Hsp25/27 phosphorylation, aberrant Hsp27 phosphorylation has been linked to several clinical conditions. This review focuses on the different Hsp25/27 kinases and phosphatases that regulate the phosphorylation pattern of Hsp25/27, and discusses the recent findings of the biological implications of these phosphorylation events in physiological and pathological processes. Novel therapeutic strategies aimed at restoring anomalous Hsp27 phosphorylation in human diseases will be presented.

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

Pyrrolo-pyrimidones: A novel class of MK2 inhibitors with potent cellular activity

Cited by 45 publications

References 16 publications

Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement

Hsp-27 expression at diagnosis predicts poor clinical outcome in prostate cancer independent of ETS-gene rearrangement

Heat shock protein 27 phosphorylation: kinases, phosphatases, functions and pathology

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

Contact Info

Product

Resources

About