Current developments in extracellular-regulated protein kinase (ERK1/2) inhibitors

Niu, Yuzhen; Ji, Hong‐Fang

doi:10.1016/j.drudis.2022.01.012

Cited by 7 publications

(3 citation statements)

References 80 publications

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“…[38,41] ERK2 plays a positive role in controlling Ras-dependent cell signaling and proliferation, but is independent of ERK1 kinase activity. [39,42] Molecular docking and western blot analysis indicated that the antiinflammatory activity of FA-Exo/R+C was achieved by blocking pNF-𝜅B and pERK2. These data suggested that FA-Exo/R+C significantly inhibited the inflammation and proliferation of M1 macrophages by regulating of NF-𝜅B and ERK1/2 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy with Resveratrol and Celastrol Using Folic Acid‐Functionalized Exosomes Enhances the Therapeutic Efficacy of Sepsis

Zheng,

Xing,

Sun

et al. 2023

Adv Healthcare Materials

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Overactivated macrophages are a prominent feature of many inflammatory and autoimmune diseases, including sepsis. Attention and regulation of macrophages activity is of great significance for sepsis treatment. Here we showed that folic acid‐functionalized exosomes accumulated in the lung of septic mice and specifically targeted inflammatory macrophages. We therefore designed FA‐functionalized exosomes co‐loaded with resveratrol (an anti‐inflammatory polyphenol) and celastrol (an immunosuppressive pentacyclic triterpenoid; FA‐Exo/R+C), which exhibited powerful anti‐inflammatory and immunosuppressive activities against LPS‐stimulated macrophages in vitro by regulating NF‐κB and ERK1/2 signaling pathways. Encouraged by these positive data, the efficacy of FA‐Exo/R+C was systematically investigated in an LPS‐induced mouse sepsis model. FA‐Exo/R+C showed striking therapeutic benefits in terms of attenuated cytokine storm, reduced acute lung injury, and increased survival of septic mice by inhibiting the inflammation and proliferation of proinflammatory M1 macrophages. Importantly, multiple administrations of FA‐Exo/R+C significantly enhanced and prolonged the protective effect, and resisted re‐challenge to LPS. Collectively, the strategy of co‐delivering drugs combination through functionalized exosomes offers a new avenue for sepsis treatment.This article is protected by copyright. All rights reserved

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Section: Discussionmentioning

confidence: 99%

Combination Therapy with Resveratrol and Celastrol Using Folic Acid‐Functionalized Exosomes Enhances the Therapeutic Efficacy of Sepsis

Zheng,

Xing,

Sun

et al. 2023

Adv Healthcare Materials

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“…Aberrant activation of ERK1/2 is closely related to the progression and metastasis of a variety of human cancers . ERK1/2 mainly acts as the downstream component of the RAS-RAF-MEK-ERK signaling pathway that transmits extracellular signals from growth factors and mitogens and is one of the most commonly mutated pathways in tumors. , RAS, RAF, and MEK mutations have been widely identified in various human cancers, and all these upstream mutations can lead to ERK1/2 hyperactivation.…”

Section: Oncogenic Roles Of Erk1/2mentioning

confidence: 99%

Targeting Extracellular Signal-Regulated Protein Kinase 1/2 (ERK1/2) in Cancer: An Update on Pharmacological Small-Molecule Inhibitors

Chen

et al. 2022

J. Med. Chem.

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Extracellular signal-regulated protein kinase 1/2 (ERK1/2), the only known substrate of MEK1/2, is located downstream of the RAS-RAF-MEK-ERK (MAPK) pathway and is associated with the abnormal activation and poor prognosis of cancer. To date, several small-molecule inhibitors of RAS, RAF, and MEK have been reported to make rapid advances in cancer therapy; however, acquired resistance still occurs, thereby weakening the therapeutic efficacy of these inhibitors. Recently, selective inhibition of ERK1/2 has been regarded as a potential cancer therapeutic strategy that can not only effectively block the MAPK pathway but also overcome drug resistance caused by upstream mutations in RAS, RAF, and MEK. Herein, we summarize the oncogenic roles, key signaling network, and the single- and dual-target inhibitors of ERK1/2 in preclinical and clinical trials. Together, these inspiring findings shed new light on the discovery of more small-molecule inhibitors of ERK1/2 as candidate drugs to improve cancer therapeutics.

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“…ERK regulates the transcriptional activation of Elk-1, activating transcription factor (ATF), Ap-1, c-fos, and c-Jun in cells, and participates in various biological responses such as cell proliferation and differentiation, morphological maintenance, skeleton construction, apoptosis, and carcinogenesis. 74,75 ERKs are the key protein kinase nodes involved in Ras-Raf-MEK-ERK-MAP kinase sig-naling pathway, and involved in many biological processes including cell proliferation and apoptosis, immune response, nervous system function, and RNA synthesis and processing. 76 There are four drugs targeting ERKs family in the PKIDB or in FDA approved drugs 5 : dabrafenib, ravoxertinib, tomivosertib, and ulixertinib.…”

Section: Erks Familymentioning

confidence: 99%

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

Pang

Wang

Qin

et al. 2022

MedComm

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Protein phosphorylation is an important post‐transcriptional modification involving an extremely wide range of intracellular signaling transduction pathways, making it an important therapeutic target for disease intervention. At present, numerous drugs targeting protein phosphorylation have been developed for the treatment of various diseases including malignant tumors, neurological diseases, infectious diseases, and immune diseases. In this review article, we analyzed 303 small‐molecule protein phosphorylation kinase inhibitors (PKIs) registered and participated in clinical research obtained in a database named Protein Kinase Inhibitor Database (PKIDB), including 68 drugs approved by the Food and Drug Administration of the United States. Based on previous classifications of kinases, we divided these human protein phosphorylation kinases into eight groups and nearly 50 families, and delineated their main regulatory pathways, upstream and downstream targets. These groups include: protein kinase A, G, and C (AGC) and receptor guanylate cyclase (RGC) group, calmodulin‐dependent protein kinase (CaMK) group, CMGC [Cyclin‐dependent kinases (CDKs), Mitogen‐activated protein kinases (MAPKs), Glycogen synthase kinases (GSKs), and C dc2‐like kinases (CLKs)] group, sterile (STE)‐MAPKs group, tyrosine kinases (TK) group, tyrosine kinase‐like (TKL) group, atypical group, and other groups. Different groups and families of inhibitors stimulate or inhibit others, forming an intricate molecular signaling regulatory network. This review takes newly developed new PKIs as breakthrough point, aiming to clarify the regulatory network and relationship of each pathway, as well as their roles in disease intervention, and provide a direction for future drug development.

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Current developments in extracellular-regulated protein kinase (ERK1/2) inhibitors

Cited by 7 publications

References 80 publications

Combination Therapy with Resveratrol and Celastrol Using Folic Acid‐Functionalized Exosomes Enhances the Therapeutic Efficacy of Sepsis

Combination Therapy with Resveratrol and Celastrol Using Folic Acid‐Functionalized Exosomes Enhances the Therapeutic Efficacy of Sepsis

Targeting Extracellular Signal-Regulated Protein Kinase 1/2 (ERK1/2) in Cancer: An Update on Pharmacological Small-Molecule Inhibitors

Role of protein phosphorylation in cell signaling, disease, and the intervention therapy

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