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Mechanistically detailed systems biology modeling of the HGF/Met pathway in hepatocellular carcinoma
2019
npj Systems Biology and Applications
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Overall, the model provides a valuable framework for studying the efficacy of drugs targeting receptor tyrosine kinase interaction with integrins, and identification of synergistic drug combinations for ...
Furthermore, the model predicted patient-specific synergy and antagonism of efficacy and potency for combination of AXT050 with sorafenib, cabozantinib, and rilotumumab. ...
., and E.J.F., as well as R01CA138264 to A. S.P. ...
doi:10.1038/s41540-019-0107-2
pmid:31452933
pmcid:PMC6697704
fatcat:biygsllop5gildcu75ckuns47a
ER stress and UPR activation in glioblastoma: identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation
2019
Cell Death and Disease
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In conclusion, we provide evidence that PERK signaling contributes to the prognoses of primary GBM patients and identified PERK as a novel regulator of SOX2 expression and GSC differentiation. ...
Here we explored if the ER stress/unfolded protein response (UPR) is involved in the pathophysiology of GBM and may provide novel therapeutic targets. ...
This research was funded by 617-2013 call Colciencias, Colombia and the Graduate School of Medical Sciences, University of Groningen. ...
doi:10.1038/s41419-019-1934-1
pmid:31534165
pmcid:PMC6751174
fatcat:scj4whzn25ed5awk2xqozpito4
Identification and Characterization of PERK Activators by Phenotypic Screening and Their Effects on NRF2 Activation
2015
PLoS ONE
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To identify novel PERK activators through phosphorylation of eIF2α, a focused set of 8,400 compounds was screened in this assay at 10 µM. A number of hits were identified and validated. ...
Specificity of these compounds in activating PERK was demonstrated with a PERK specific inhibitor and in PERK knockout mouse embryonic fibroblast (MEF) cells. ...
Jeff Axten for the supply of the PERK specific inhibitor and its closely related analog, as well as his suggestions for the manuscript. ...
doi:10.1371/journal.pone.0119738
pmid:25780921
pmcid:PMC4363567
fatcat:4x3w65okorcunptqk7z3mcr4ia
Genetic or Pharmacological Reduction of PERK Enhances Cortical-Dependent Taste Learning
2014
Journal of Neuroscience
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Both genetic reduction of PERK expression and pharmacological inhibition of its activity reduced p-eIF2␣ levels and enhanced novel taste learning and conditioned taste aversion, but not memory retrieval ...
Following identification of PERK as the major kinase to determine basal levels of p-eIF2␣ in primary neuronal cultures, we tested its function as a physiological constraint of memory consolidation in the ...
To test the effect of PERK inhibition on the behavioral level, PERK inhibitor (1 l of GSK2606414, 100 nM) was injected to the IC 20 min before exposure to a novel taste, in either an incidental taste learning ...
doi:10.1523/jneurosci.2117-14.2014
pmid:25355215
fatcat:k7eejgelzzfkrfdt62db2hgc5a
Small molecule strategies to harness the unfolded protein response: where do we go from here?
2020
Journal of Biological Chemistry
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The UPR is comprised of three signaling pathways activated downstream of the ER membrane proteins IRE1, ATF6, and PERK. ...
Recently, there has been significant progress in the identification and characterization of UPR modulating compounds, providing new opportunities to probe the pathologic and potentially therapeutic implications ...
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Conflict of interest-R. L. ...
doi:10.1074/jbc.rev120.010218
pmid:32887796
pmcid:PMC7667976
fatcat:kf4xfk6irrhffbv34ottivmzb4
Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors
2014
Pigment Cell & Melanoma Research
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Utilizing whole-exome sequencing and a novel forward genetic screening method, we identified a novel BRAF L505H mutation in BRAF V600K melanoma cells, N-terminal BRAF truncations, and CRAF overexpression ...
Here we report the discovery of a novel BRAF mutation that confers resistance to PLX4032 employing whole-exome sequencing of drug-resistant BRAF V600K melanoma cells. ...
Gideon Bollag, Plexxikon, for the BRAF inhibitors PLX4032, PLX7904, and PLX8394. ...
doi:10.1111/pcmr.12197
pmid:24283590
pmcid:PMC4065135
fatcat:kd6ewnvpd5g23ezuifvmv33wpe
Characterization of a Novel PERK Kinase Inhibitor with Antitumor and Antiangiogenic Activity
2013
Cancer Research
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GSK2656157 is an ATP-competitive inhibitor of PERK enzyme activity with an IC 50 of 0.9 nmol/L. It is highly selective for PERK with IC 50 values >100 nmol/L against a panel of 300 kinases. ...
We have identified a first-in-class, small molecule inhibitor of the eukaryotic initiation factor 2-alpha kinase 3 (EIF2AK3) or PERK, one of the three mediators of UPR signaling. ...
Further medicinal chemistry optimization led to the identification of GSK2656157 (Table 1) , a potent and selective inhibitor of PERK kinase with an IC 50 of 0.9 nmol/L. ...
doi:10.1158/0008-5472.can-12-3109
pmid:23333938
fatcat:vsfhgkr3t5hdxaq3z3rvxtogu4
Endorepellin evokes an angiostatic stress signaling cascade in endothelial cells
2020
Journal of Biological Chemistry
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To functionally validate these findings, we utilized an ex vivo model of angiogenesis. ...
In this study, we discovered that soluble endorepellin activates the canonical stress signaling pathway consisting of PERK, eIF2α, ATF4 and GADD45α. ...
Mongiat for providing LG1/2 in the initial stages of this work, S. Buraschi for help with immunostaining, and T. Neill for critical reading of the manuscript. ...
doi:10.1074/jbc.ra120.012525
pmid:32205445
pmcid:PMC7212646
fatcat:hm5zlnho4rgsjb2eyeh276sdka
Cellular stress induces cap-independent alpha-enolase/MBP-1 translation
2015
FEBS Letters
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Although several lines of evidence indicate that MBP-1 acts as a tumor suppressor, the cellular mechanisms and signaling pathways underlying MBP-1 expression still remain largely elusive. ...
Here, we demonstrate that induced cell stresses promote MBP-1 expression through the AKT/PERK/eIF2a signaling axis. ...
RBNE08YYBM) to S.F. and A.G., University of Palermo (n. 2014-ATE-0185) to S.F., and by a Grant (to A.G.) from the CNR Project ''FaReBio di Qualità'', financed by the Italian Ministry of Economy and Finance ...
doi:10.1016/j.febslet.2015.06.030
pmid:26144282
fatcat:pux3wuq4iraotf7nvcearoh7da
The Unfolded Protein Response: A Novel Component of the Hypoxic Stress Response in Tumors
2005
Molecular Cancer Research
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Pancreatic ER kinase (PKR-like ER kinase) regulates the translational branch of the UPR and is also important in the growth of tumors. ...
XBP-1 is a critical transcriptional regulator of this process and is required for tumor growth. ...
The use of small interfering RNA techniques and the identification of selective inhibitors of PERK and Ire1 that enable a ''chemical genetic'' approach will be indispensable in determining the function ...
doi:10.1158/1541-7786.mcr-05-0221
pmid:16317085
fatcat:sf6lenzgi5e2xdb7zg4o52tzua
A chromatin modifier genetic screen identifies SIRT2 as a modulator of response to targeted therapies through the regulation of MEK kinase activity
2014
Oncogene
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SIRT2 loss also conferred resistance to BRAF and MEK inhibitors in BRAF mutant melanoma and KRAS mutant colon cancers, respectively. ...
colon and lung cancer. ...
We thank Gerrit Hooiger and Marc van de Vijver (AMC, Amsterdam) for assistance in staining tissue microarrays and Alberto Bardelli for the kind gift of the Difi cells. ...
doi:10.1038/onc.2013.588
pmid:24469059
fatcat:d5t4m3am7favdaqtuhh2qn6xla
Novel Oncology Drug Development Strategies in the Era of Personalised Medicine
[chapter]
2011
Drug Discovery and Development - Present and Future
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There is therefore a critical need to integrate and validate novel biomarkers into drug development from the earliest stages of evaluation, incorporating tumour and non-tumour tissue samples to apply these ...
of PI3K and MEK inhibitors (Jiang et al., 2010) . ...
The drug discovery and development process relies on the utilization of relevant and robust tools, methods, models, and validated biomarkers that are predictive of clinical effects in terms of diagnosis ...
doi:10.5772/26984
fatcat:yed5t777ybelfpniid2s6vxunq
Inositol-requiring Enzyme 1 Inhibits Respiratory Syncytial Virus Replication
2014
Journal of Biological Chemistry
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Significance: Identification of a novel regulator of RSV replication may have therapeutic implications. . 2 The abbreviations used are: RSV, respiratory syncytial virus; ER, endoplasmic reticulum; PERK ...
Conclusion: ER stress may be a novel cellular anti-RSV defense mechanism. ...
Identification of novel host cellular responses that play a role in the pathogenesis of RSV infection is needed for therapeutic development. ...
doi:10.1074/jbc.m113.510594
pmid:24497642
pmcid:PMC3953267
fatcat:aouvvfsrlnga7c7aez6ccd6nv4
Endoplasmic Reticulum Stress Increases DUSP5 Expression via PERK-CHOP Pathway, Leading to Hepatocyte Death
2019
International Journal of Molecular Sciences
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The induction of DUSP5 by ER stress was blocked by either treatment with a chemical inhibitor of the protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway, or knockdown of C/EBP homologous ...
Treatment of ER stress inducers enhanced DUSP5 expression in hepatocytes, which was validated in vivo condition. ...
Acknowledgments: We thank Sang Geon Kim (Seoul National University, Republic of Korea) for allowing use of liver samples from the animal models of liver diseases or ER stress. ...
doi:10.3390/ijms20184369
pmid:31491992
pmcid:PMC6770509
fatcat:alcipktl25hh3fh57jenej34t4
The PERK inhibitor GSK2606414 enhances reovirus infection in head and neck squamous cell carcinoma via an ATF4-dependent mechanism
2020
Molecular Therapy: Oncolytics
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Our work identifies a novel approach to enhance the efficacy and replication of reovirus in a therapeutic setting. ...
Knockdown of eIF2a kinases PERK, GCN2, and PKR revealed eIF2a-ATF4 reporter activity was dependent on either PERK or GCN2. ...
validating Tet-pLKO shRNA knockdown of PERK, GCN2, and PKR after 96 h of doxycycline treatment. ...
doi:10.1016/j.omto.2020.01.001
pmid:32128359
pmcid:PMC7047134
fatcat:46ag4amo2jfd3lcusyxe4uubji
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