A Small Molecule Targeting Human MEK1/2 Enhances ERK and p38 Phosphorylation under Oxidative Stress or with Phenothiazines

Small molecules are routinely used to inhibit protein kinases, but modulators capable of enhancing kinase activity are rare. We have previously shown that the small molecule INR119, designed as an inhibitor of MEK1/2, will enhance the activity of its fission yeast homologue, Wis1, under oxidative st...

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Bibliographic Details
Published in:Life (Basel, Switzerland) Switzerland), 2021-03, Vol.11 (4), p.297
Main Authors: Otręba, Michał, Sjölander, Johanna Johansson, Grøtli, Morten, Sunnerhagen, Per
Format: Article
Language:English
Subjects:
Apoptosis
Bax protein
Biochemistry and Molecular Biology
Biokemi och molekylärbiologi
Breast cancer
Cancer therapies
Cell Biology
Cellbiologi
Communication
Cytokines
Extracellular signal-regulated kinase
Fission
Glycerol
Homology
Hydrogen peroxide
Kinases
Läkemedelskemi
MAP kinase pathways
Medicinal Chemistry
Modulators
mRNA
Oxidative stress
p53 Protein
Penicillin
Phenothiazines
Phosphorylation
Protein kinase
Proteins
Psychotropic drugs
redox signalling
small molecule kinase modulator
Yeast
Yeasts
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Summary:Small molecules are routinely used to inhibit protein kinases, but modulators capable of enhancing kinase activity are rare. We have previously shown that the small molecule INR119, designed as an inhibitor of MEK1/2, will enhance the activity of its fission yeast homologue, Wis1, under oxidative stress. To investigate the generality of these findings, we now study the effect of INR119 in human cells under similar conditions. Cells of the established breast cancer line MCF-7 were exposed to H O or phenothiazines, alone or combined with INR119. In line with the previous results in fission yeast, the phosphorylation of the MAPKs ERK and p38 increased substantially more with the combination treatment than by H O or phenothiazines, whereas INR119 alone did not affect phosphorylation. We also measured the mRNA levels of and , known to be affected by ERK and p38 activity. Similarly, the combination of INR119 and phenothiazines increased both mRNAs to higher levels than for phenothiazines alone. In conclusion, the mechanism of action of INR119 on its target protein kinase may be conserved between yeast and humans.
ISSN:2075-1729
2075-1729
DOI:10.3390/life11040297