Rigosertib inhibits MEK1–ERK pathway and alleviates lipopolysaccharide‐induced sepsis

Wang, Yin; Du, Pengfei; Jiang, Donghui

doi:10.1002/iid3.458

Cited by 4 publications

(4 citation statements)

References 34 publications

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“…The RAS-RAF-MEK-ERK signaling axis drives cytokine production in macrophages upon LPS activation, and MEK1/2 inhibitors have been shown to block the release of cytokines and decrease mortality in mouse models of sepsis. [24][25][26][27] Studies have also demonstrated the effectiveness of MEK1/2 inhibitors in the treatment of autoimmune diseases such as collagen induced arthritis, rheumatoid arthritis, and lung diseases. [25,[27][28][29] In addition to the seven MEK1/2 inhibitors, five other kinase inhibitors also scored significantly in the secondary assay and modulated the expression of specific cytokines.…”

Section: Discussionmentioning

confidence: 99%

High‐Content Image‐Based Screening and Deep Learning for the Detection of Anti‐Inflammatory Drug Leads

Lau,

Mair,

Rabbitts

et al. 2023

ChemBioChem

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We developed a high‐content image‐based screen that utilizes the pro‐inflammatory stimulus lipopolysaccharide (LPS) and murine macrophages (RAW264.7) with the goal of enabling the identification of novel anti‐inflammatory lead compounds. We screened 2,259 bioactive compounds with annotated mechanisms of action (MOA) to identify compounds that block the LPS‐induced phenotype in macrophages. We utilized a set of seven fluorescence microscopy probes to generate images that were used to train and optimize a deep neural network classifier to distinguish between unstimulated and LPS‐stimulated macrophages. The top hits from the deep learning classifier were validated using a linear classifier trained on individual cells and subsequently investigated in a multiplexed cytokine secretion assay. All 12 hits significantly modulated the expression of at least one cytokine upon LPS stimulation. Seven of these were allosteric inhibitors of the mitogen‐activated protein kinase kinase (MEK1/2) and showed similar effects on cytokine expression. This deep learning morphological assay identified compounds that modulate the innate immune response to LPS and may aid in identifying new anti‐inflammatory drug leads.

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Section: Discussionmentioning

confidence: 99%

High‐Content Image‐Based Screening and Deep Learning for the Detection of Anti‐Inflammatory Drug Leads

Lau,

Mair,

Rabbitts

et al. 2023

ChemBioChem

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“…Whether this effect on CD40 is due to Ras-Raf signaling or to the dependence of CD40 function upon ROS induction [43,44] is not yet clear. Finally, in a non-cancer related study, Wang et al studied lipopolysaccharide-induced sepsis, using rigosertib as a MEK1-ERK signaling inhibitor, concluding that it prevented the production of proinflammatory cytokines induced by LPS by disrupting the activation of the MEK1-ERK signaling axis [45].…”

Section: Rigosertib As a Ras Mimetic And Ras-raf-mek Axis Inhbitormentioning

confidence: 99%

Lights and Shadows on the Cancer Multi-Target Inhibitor Rigosertib (ON-01910.Na)

Monfort-Vengut

Cárcer

2023

Pharmaceutics

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Rigosertib (ON-01910.Na) is a small-molecule member of the novel synthetic benzyl-styryl-sulfonate family. It is currently in phase III clinical trials for several myelodysplastic syndromes and leukemias and is therefore close to clinical translation. The clinical progress of rigosertib has been hampered by a lack of understanding of its mechanism of action, as it is currently considered a multi-target inhibitor. Rigosertib was first described as an inhibitor of the mitotic master regulator Polo-like kinase 1 (Plk1). However, in recent years, some studies have shown that rigosertib may also interact with the PI3K/Akt pathway, act as a Ras–Raf binding mimetic (altering the Ras signaling pathway), as a microtubule destabilizing agent, or as an activator of a stress-induced phospho-regulatory circuit that ultimately hyperphosphorylates and inactivates Ras signaling effectors. Understanding the mechanism of action of rigosertib has potential clinical implications worth exploring, as it may help to tailor cancer therapies and improve patient outcomes.

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“… 150 Intriguingly, researchers discovered in an LPS-induced sepsis mouse model that rigosertib improved the inflammatory response by inhibiting the MEK1-ERK signaling pathway. 151 In LPS-treated HUVECs and a mouse cecum ligation (CLP)-induced sepsis model, findings suggest that the upregulation of PCSK9 activates the TLR4/MyD88/NF-кB and NLRP3 pathways, inducing inflammation and resulting in endothelial dysfunction. Therefore, inhibiting PCSK9 may represent a novel strategy to improve vascular endothelial function in sepsis.…”

Section: The Role Of Endothelial Cells Inflammation In Different Dise...mentioning

confidence: 99%

Research Progress and Molecular Mechanisms of Endothelial Cells Inflammation in Vascular-Related Diseases

Xue,

Zhang,

Sun

et al. 2023

JIR

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Endothelial cells (ECs) are widely distributed inside the vascular network, forming a vital barrier between the bloodstream and the walls of blood vessels. These versatile cells serve myriad functions, including the regulation of vascular tension and the management of hemostasis and thrombosis. Inflammation constitutes a cascade of biological responses incited by biological, chemical, or physical stimuli. While inflammation is inherently a protective mechanism, dysregulated inflammation can precipitate a host of vascular pathologies. ECs play a critical role in the genesis and progression of vascular inflammation, which has been implicated in the etiology of numerous vascular disorders, such as atherosclerosis, cardiovascular diseases, respiratory diseases, diabetes mellitus, and sepsis. Upon activation, ECs secrete potent inflammatory mediators that elicit both innate and adaptive immune reactions, culminating in inflammation. To date, no comprehensive and nuanced account of the research progress concerning ECs and inflammation in vascular-related maladies exists. Consequently, this review endeavors to synthesize the contributions of ECs to inflammatory processes, delineate the molecular signaling pathways involved in regulation, and categorize and consolidate the various models and treatment strategies for vascular-related diseases. It is our aspiration that this review furnishes cogent experimental evidence supporting the established link between endothelial inflammation and vascular-related pathologies, offers a theoretical foundation for clinical investigations, and imparts valuable insights for the development of therapeutic agents targeting these diseases.

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Rigosertib inhibits MEK1–ERK pathway and alleviates lipopolysaccharide‐induced sepsis

Cited by 4 publications

References 34 publications

High‐Content Image‐Based Screening and Deep Learning for the Detection of Anti‐Inflammatory Drug Leads

High‐Content Image‐Based Screening and Deep Learning for the Detection of Anti‐Inflammatory Drug Leads

Lights and Shadows on the Cancer Multi-Target Inhibitor Rigosertib (ON-01910.Na)

Research Progress and Molecular Mechanisms of Endothelial Cells Inflammation in Vascular-Related Diseases

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