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Selective Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibition by the SCH772984 Compound Attenuates In Vitro
Michal Kopczynski1, Izabela Rumienczyk1, Maria Kulecka1,2
1Department of Genetics, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.
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.
Insights
SCH772984, an ERK 1/2 inhibitor, effectively reduced inflammatory markers and improved survival in preclinical sepsis models. This study highlights its potential as a novel sepsis therapeutic by defining its molecular action.
Area of Science:
- Pharmacology
- Immunology
- Genomics
Background:
- Sepsis is a critical global health issue with high mortality, lacking effective targeted treatments.
- Current sepsis management relies on supportive care, as clinical trials for specific pharmacotherapies have yielded disappointing results.
Purpose of the Study:
- To identify novel therapeutic agents for sepsis through drug repurposing targeting epigenetic enzymes.
- To investigate the efficacy of extracellular signal-regulated kinase (ERK) 1/2 inhibitor SCH772984 in preclinical models of sepsis.
Main Methods:
- Supervised drug repurposing screen using lipopolysaccharide (LPS)-stimulated RAW264.7 cells and an AlphaLisa assay for tumor necrosis factor-alpha (TNFa).
- RNA sequencing (RNA-Seq) to analyze gene expression changes in response to SCH772984 treatment in vitro and in vivo.
- Assessment of SCH772984 efficacy in LPS-induced endotoxemia and cecal ligation and puncture (CLP) mouse models of sepsis.
Main Results:
- SCH772984 was identified as an effective inhibitor of TNFa production in vitro.
- RNA-Seq analysis revealed that SCH772984 suppresses immune system-related cellular pathways.
- SCH772984 treatment significantly improved survival rates in mouse sepsis models and reduced Ccl2/Mcp1 plasma levels.
- In vivo transcriptomic analysis showed downregulation of immune response and platelet activation pathways, alongside upregulation of extracellular matrix organization and retinoic acid signaling.
Conclusions:
- SCH772984 demonstrates significant therapeutic potential for sepsis by modulating key inflammatory pathways.
- Transcriptome signatures of SCH772984 action provide insights into its mechanism of improving sepsis outcomes.
- This study validates SCH772984 as a promising drug candidate for sepsis treatment.
