Selective Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibition by the SCH772984 Compound Attenuates In Vitro and In Vivo Inflammatory Responses and Prolongs Survival in Murine Sepsis Models.

Abstract

Sepsis is the leading cause of death in intensive care units worldwide. Current treatments of sepsis are largely supportive and clinical trials using specific pharmacotherapy for sepsis have failed to improve outcomes. Here, we used the lipopolysaccharide (LPS)-stimulated mouse RAW264.7 cell line and AlphaLisa assay for TNFa as a readout to perform a supervised drug repurposing screen for sepsis treatment with compounds targeting epigenetic enzymes, including kinases. We identified the SCH772984 compound, an extracellular signal-regulated kinase (ERK) 1/2 inhibitor, as an effective blocker of TNFa production in vitro. RNA-Seq of the SCH772984-treated RAW264.7 cells at 1, 4, and 24 h time points of LPS challenge followed by functional annotation of differentially expressed genes highlighted the suppression of cellular pathways related to the immune system. SCH772984 treatment improved survival in the LPS-induced lethal endotoxemia and cecal ligation and puncture (CLP) mouse models of sepsis, and reduced plasma levels of Ccl2/Mcp1. Functional analyses of RNA-seq datasets for kidney, lung, liver, and heart tissues from SCH772984-treated animals collected at 6 h and 12 h post-CLP revealed a significant downregulation of pathways related to the immune response and platelets activation but upregulation of the extracellular matrix organization and retinoic acid signaling pathways. Thus, this study defined transcriptome signatures of SCH772984 action in vitro and in vivo, an agent that has the potential to improve sepsis outcome.

• Authors: Michal Kopczynski, Izabela Rumienczyk, Maria Kulecka, Małgorzata Statkiewicz, Kazimiera Pysniak, Zuzanna Sandowska-Markiewicz, Urszula Wojcik-Trechcinska, Krzysztof Goryca, Karolina Pyziak, Eliza Majewska, Magdalena Masiejczyk, Katarzyna Wojcik-Jaszczynska, Tomasz Rzymski, Karol Bomsztyk, Jerzy Ostrowski, Michal Mikula
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 19 (Sep 22 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 34638546 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Ccl2 protein, mouse
• Chemokine CCL2
• Indazoles
• Lipopolysaccharides
• MK-8353
• Piperazines
• Pyridines
• Pyrrolidines
• SCH772984
• Triazoles
• Tumor Necrosis Factor-alpha
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Cell Line
• Chemokine CCL2 (blood)
• Disease Models, Animal
• Down-Regulation (drug effects)
• Drug Repositioning
• Endotoxemia (drug therapy, mortality)
• Gene Expression Regulation (drug effects)
• Indazoles (pharmacology)
• Lipopolysaccharides (toxicity)
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors)
• Piperazines (pharmacology)
• Platelet Activation (drug effects)
• Pyridines (pharmacology)
• Pyrrolidines (pharmacology)
• RAW 264.7 Cells
• Transcriptome (genetics)
• Triazoles (pharmacology)
• Tumor Necrosis Factor-alpha (biosynthesis)