Unexpected Reaction of 2-Alkylsulfanylimidazoles to Imidazol-2-ones: Pyridinylimidazol-2-ones as Novel Potent p38α Mitogen-Activated Protein Kinase Inhibitors

2010 ◽  
Vol 53 (12) ◽  
pp. 4798-4802 ◽  
Author(s):  
Pierre Koch ◽  
Stefan Laufer
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Unexpected Reaction ◽  
Mitogen Activated Protein

scholarly journals Mitogen-activated protein kinase-mediated phosphorylation of peroxiredoxin 6 regulates its phospholipase A2 activity

2009 ◽  
Vol 419 (3) ◽  
pp. 669-679 ◽  
Author(s):  
Yongzheng Wu ◽  
Sheldon I. Feinstein ◽  
Yefim Manevich ◽  
Ibrul Chowdhury ◽  
Jhang Ho Pak ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Phospholipase A2 ◽  
Kinase Inhibitors ◽  
Phosphorylation Site ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Alveolar Type ◽  
Peroxiredoxin 6 ◽  
Mitogen Activated Protein

Prdx6 (peroxiredoxin 6), a bifunctional protein with both GSH peroxidase and PLA2 (phospholipase A2) [aiPLA2 (acidic calcium-independent PLA2)] activities, is responsible for the metabolism of lung surfactant phospholipids. We propose that the aiPLA2 activity of the enzyme is regulated through phosphorylation. Incubation of isolated rat alveolar type II cells (AECII) with PMA, a PKC (protein kinase C) agonist, had no effect on Prdx6 expression but led to ∼75% increase in aiPLA2 activity that was abolished by pretreatment of cells with the MAPK (mitogen-activated protein kinase) inhibitors, SB202190 or PD98059. Prdx6 phosphorylation after incubation of AECII with PMA was demonstrated by autoradiography after immunoprecipitation with either anti-phosphothreonine o-phosphoserine antibodies. in vitro, several active isoforms of ERK (extracellular-signal-regulated kinase) and p38 phosphorylated Prdx6, resulting in an 11-fold increase in aiPLA2 activity. The increased activity was calcium-independent and was abolished by the aiPLA2 inhibitors, surfactant protein A and hexadecyl-3-trifluorethylglycero-sn-2-phospho-methanol (MJ33). The peroxidase activity of Prdx6 was unaffected by phosphorylation. Mass spectroscopic analysis of in vitro phosphorylated Prdx6 showed a unique phosphorylation site at Thr-177 and mutation of this residue abolished protein phosphorylation and the increase in MAPK-mediated activity. These results show that the MAPKs can mediate phosphorylation of Prdx6 at Thr-177 with a consequent marked increase in its aiPLA2 activity.

scholarly journals An optimized and versatile synthesis to pyridinylimidazole-type p38α mitogen activated protein kinase inhibitors

2015 ◽  
Vol 13 (43) ◽  
pp. 10699-10704 ◽  
Author(s):  
Ahmed El-Gokha ◽  
Stefan A. Laufer ◽  
Pierre Koch
Keyword(s):  
Protein Kinase ◽  
Map Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Synthetic Approach ◽  
Mitogen Activated Protein ◽  
P38α Map Kinase

An optimized and diverse synthetic approach for the preparation of potent pyridinylimidazole-based p38α MAP kinase inhibitors is reported.

scholarly journals Ocular Toxicity of Mitogen-Activated Protein Kinase Inhibitors

JAMA Oncology ◽  
2017 ◽  
Vol 3 (2) ◽  
pp. 275 ◽  
Author(s):  
Robert M. J. Purbrick ◽  
Olaoluwakitan A. Osunkunle ◽  
Denis C. Talbot ◽  
Susan M. Downes
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Ocular Toxicity ◽  
Mitogen Activated Protein

scholarly journals Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

2020 ◽  
Vol 13 (1) ◽  
pp. 9 ◽  
Author(s):  
Sandeep Kumar ◽  
Daniel R. Principe ◽  
Sunil Kumar Singh ◽  
Navin Viswakarma ◽  
Gautam Sondarva ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Tumor Cells ◽  
Cell Biology ◽  
Kinase Inhibitors ◽  
Mapk Signaling ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Wide Range ◽  
Mitogen Activated Protein

Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several components of the MAPK signaling network have been proposed as viable targets for cancer therapy. However, the contributions of MAPK signaling extend well beyond the tumor cells, and several MAPK effectors have been identified as key mediators of the tumor microenvironment (TME), particularly with respect to the local immune infiltrate. In fact, a blockade of various MAPK signals has been suggested to fundamentally alter the interaction between tumor cells and T lymphocytes and have been suggested a potential adjuvant to immune checkpoint inhibition in the clinic. Therefore, in this review article, we discuss the various mechanisms through which MAPK family members contribute to T-cell biology, as well as circumstances in which MAPK inhibition may potentiate or limit cancer immunotherapy.

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