Small‐Molecule Inhibitors of the ERK Signaling Pathway: Towards Novel Anticancer Therapeutics

Yap, Jeremy L.; Worlikar, Shilpa A.; MacKerell, Alexander D.; Shapiro, Paul; Fletcher, Steven

doi:10.1002/cmdc.201000354

Cited by 70 publications

(46 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Both strategies are hampered by the need by such drugs to overcome the large free energy of association between protein-protein and, to a lesser extent, protein-DNA interfaces. Nevertheless, such drugs have been found for other bZip transcription factors such as STAT3-STAT3, MYC-MAX, and JUN-FOS (Yap et al, 2011), and new small molecules are being described for NRF2-MAF. For instance, malabaricone-A is a pro-oxidant compound that overcomes leukemia resistance by targeting NRF2 (Manna et al, 2015).…”

Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

View full text Add to dashboard Cite

Section: B Protein-protein Interaction Inhibitors For Nuclear Factormentioning

confidence: 99%

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

et al. 2018

View full text Add to dashboard Cite

“…Being a central regulatory pathway, its dysregulation is involved in various pathologies and is particularly known to play a role in cancer 4,5 . Indeed, inhibitors of both Rafs and MEK1/2 have been recently developed for the treatment of melanoma 6,7 , and it is likely that specific ERK1/2 inhibitors will be developed for the same purpose as well 8 . However, despite of the widespread involvement of the ERK1/2 cascade in the induction and maintenance of cancers, the inhibitors of the cascade were proven beneficial only in B-Rafmutated melanomas (B-Raf melanomas) 9,10 .…”

mentioning

confidence: 99%

The nuclear translocation of ERK1/2 as an anticancer target

et al. 2015

View full text Add to dashboard Cite

A hallmark of the ERK1/2 functioning is their nuclear translocation, which is mainly required for the induction of proliferation. Activated ERK1/2 molecules that remain in the cytoplasm initiate other activities, including immediate feedback loops. Prevention of the nuclear translocation should therefore inhibit proliferation, without affecting cytoplasm-induced cellular processes. Here we present an NTS-derived myristoylated phosphomimetic peptide, which blocks the interaction of importin7 and ERK1/2, and consequently the nuclear translocation of the latter. In culture, the peptide induces apoptosis of melanoma cells inhibits the viability of other cancer cells, but has no effect on non-transformed, immortalized cells. It even inhibits the viability of PLX4032-and U0126-resistant melanoma cells. In xenograft models, the peptide inhibits several cancers, and acts much better than PLX4032 in preventing melanoma recurrence. This study provides a proof of concept for using the nuclear translocation of ERK1/2 as a drug target for the combat of various ERK1/2-related cancers.

show abstract

“…Further work is necessary to understand this interesting observation. The biological evaluation of compounds 1-7 confirms the usefulness of both structure-based and ligand-based computational approaches to the discovery of selective MAP kinase inhibitors that target a protein-binding site and demonstrates that in-silico drug discovery can translate into cellular activity [89]. Figure 5b).…”

Section: Extracellular Signal-regulated Kinasesmentioning

confidence: 65%

Computational Insights for the Discovery of Non-ATP Competitive Inhibitors of MAP Kinases

Schnieders¹,

Kaoud²,

Cheng³

et al. 2012

curr drug metab

View full text Add to dashboard Cite

Due to their role in cellular signaling mitogen activated protein (MAP) kinases represent targets of pharmaceutical interest. However, the majority of known MAP kinase inhibitors compete with cellular ATP and target an ATP binding pocket that is highly conserved in the 500 plus representatives of the human protein kinase family. Here we review progress toward the development of non-ATP competitive MAP kinase inhibitors for the extracellular signal regulated kinases (ERK1/2), the c-jun N-terminal kinases (JNK1/2/3) and the p38 MAPKs (α, β, γ, and δ). Special emphasis is placed on the role of computational methods in the drug discovery process for MAP kinases. Topics include recent advances in X-ray crystallography theory that improve the MAP kinase structures essential to structure-based drug discovery, the use of molecular dynamics to understand the conformational heterogeneity of the activation loop and inhibitors discovered by virtual screening. The impact of an advanced polarizable force field such as AMOEBA used in conjunction with sophisticated kinetic and thermodynamic simulation methods is also discussed.

show abstract

Small‐Molecule Inhibitors of the ERK Signaling Pathway: Towards Novel Anticancer Therapeutics

Cited by 70 publications

References 53 publications

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

The nuclear translocation of ERK1/2 as an anticancer target

Computational Insights for the Discovery of Non-ATP Competitive Inhibitors of MAP Kinases

Contact Info

Product

Resources

About