scholarly journals The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

2018 ◽  
Author(s):  
Senthilmurugan Ramalingam ◽  
Vidya P. Ramamurthy ◽  
Lalji K. Gediya ◽  
Francis N. Murigi ◽  
Puranik Purushottamachar ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Mesenchymal Transition ◽  
Eukaryotic Initiation Factor 4E ◽  
Mtorc1 Signaling ◽  
Mitogen Activated Protein ◽  
Orally Bioavailable ◽  
Tumor Growth And Metastasis

ABSTRACTCurrently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, in clinically relevant models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor and antimetastatic activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for effective treatment of patients with primary/metastatic TNBC.

scholarly journals The Novel Mnk1/2 Degrader and Apoptosis Inducer VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 299 ◽  
Author(s):  
Senthilmurugan Ramalingam ◽  
Vidya Ramamurthy ◽  
Lalji Gediya ◽  
Francis Murigi ◽  
Puranik Purushottamachar ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
In Vivo Models ◽  
Mesenchymal Transition ◽  
Mtorc1 Signaling ◽  
Orally Bioavailable

Currently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, racemic VNLG-152R and its two enantiomers (VNLG-152E1 and VNLG-152E2) in in vitro and in vivo models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader, superior to its pure enantiomers. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor (91 to 100% growth inhibition) and antimetastatic (~80% inhibition) activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for the effective treatment of patients with primary/metastatic TNBC.

scholarly journals Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

2020 ◽  
Vol 21 (8) ◽  
pp. 2967
Author(s):  
Celia Pinto-Díez ◽  
Raquel Ferreras-Martín ◽  
Rebeca Carrión-Marchante ◽  
Víctor M. González ◽  
María Elena Martín
Keyword(s):  
Map Kinases ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor 4E ◽  
Polypyrimidine Tract Binding Protein ◽  
Hematological Cancers ◽  
Mitogen Activated Protein ◽  
Specific Proteins ◽  
Nuclear Ribonucleoprotein

The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are involved in oncogenic transformation and can promote metastasis and tumor progression. In human cells, there are four MNKs isoforms (MNK1a/b and MNK2a/b), derived from two genes by alternative splicing. These kinases play an important role controlling the expression of specific proteins involved in cell cycle, cell survival and cell motility via eukaryotic initiation factor 4E (eIF4E) regulation, but also through other substrates such as heterogeneous nuclear ribonucleoprotein A1, polypyrimidine tract-binding protein-associated splicing factor and Sprouty 2. In this review, we provide an overview of the role of MNK in human cancers, describing the studies conducted to date to elucidate the mechanism involved in the action of MNKs, as well as the development of MNK inhibitors in different hematological cancers and solid tumors.

scholarly journals A Twist-Snail Axis Critical for TrkB-Induced Epithelial-Mesenchymal Transition-Like Transformation, Anoikis Resistance, and Metastasis

2009 ◽  
Vol 29 (13) ◽  
pp. 3722-3737 ◽  
Author(s):  
Marjon A. Smit ◽  
Thomas R. Geiger ◽  
Ji-Ying Song ◽  
Inna Gitelman ◽  
Daniel S. Peeper
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Lung Metastases ◽  
Cancer Prognosis ◽  
Mitogen Activated Protein Kinase ◽  
Morphological Transformation ◽  
Anoikis Resistance ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein ◽  
Growth Of Tumor ◽  
Kinase Pathway

ABSTRACT In a genomewide anoikis suppression screen for metastasis genes, we previously identified the neurotrophic receptor tyrosine kinase TrkB. In mouse xenografts, activated TrkB caused highly invasive and metastatic tumors. Here, we describe that TrkB also induces a strong morphological transformation, resembling epithelial-mesenchymal transition (EMT). This required TrkB kinase activity, a functional mitogen-activated protein kinase pathway, suppression of E-cadherin, and induction of Twist, a transcription factor contributing to EMT and metastasis. RNA interference (RNAi)-mediated Twist depletion blocked TrkB-induced EMT-like transformation, anoikis suppression, and growth of tumor xenografts. By searching for essential effectors of TrkB-Twist signaling, we found that Twist induces Snail, another EMT regulator associated with poor cancer prognosis. Snail depletion impaired EMT-like transformation and anoikis suppression induced by TrkB, but in contrast to Twist depletion, it failed to inhibit tumor growth. Instead, Snail RNAi specifically impaired the formation of lung metastases. Epistasis experiments suggested that Twist acts upstream from Snail. Our results demonstrate that TrkB signaling activates a Twist-Snail axis that is critically involved in EMT-like transformation, tumorigenesis, and metastasis. Moreover, our data shed more light on the epistatic relationship between Twist and Snail, two key transcriptional regulators of EMT and metastasis.

scholarly journals The Roles of Mitogen-Activated Protein Kinase Pathways in TGF-β-Induced Epithelial-Mesenchymal Transition

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Ting Gui ◽  
Yujing Sun ◽  
Aiko Shimokado ◽  
Yasuteru Muragaki
Keyword(s):  
Growth Factors ◽  
Protein Kinase ◽  
Epithelial Mesenchymal Transition ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Important Process ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein ◽  
And Function ◽  
External Signals

The mitogen-activated protein kinase (MAPK) pathway allows cells to interpret external signals and respond appropriately, especially during the epithelial-mesenchymal transition (EMT). EMT is an important process during embryonic development, fibrosis, and tumor progression in which epithelial cells acquire mesenchymal, fibroblast-like properties and show reduced intercellular adhesion and increased motility. TGF-β signaling is the first pathway to be described as an inducer of EMT, and its relationship with the Smad family is already well characterized. Studies of four members of the MAPK family in different biological systems have shown that the MAPK and TGF-β signaling pathways interact with each other and have a synergistic effect on the secretion of additional growth factors and cytokines that in turn promote EMT. In this paper, we present background on the regulation and function of MAPKs and their cascades, highlight the mechanisms of MAPK crosstalk with TGF-β signaling, and discuss the roles of MAPKs in EMT.

Mnk inhibitors: a patent review

2021 ◽  
Vol 10 (1) ◽  
pp. 25-35
Author(s):  
Ahmed M Abdelaziz ◽  
Mingfeng Yu ◽  
Shudong Wang
Keyword(s):  
Mrna Translation ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Research Articles ◽  
Eukaryotic Initiation Factor 4E ◽  
Current State ◽  
Patent Review ◽  
Hematological Cancers ◽  
Mitogen Activated Protein ◽  
Patent Applications

The alteration of mRNA translation has a crucial role in defining the changes in cellular proteome. The phosphorylation of eukaryotic initiation factor 4E by mitogen-activated protein kinase-interacting kinases (Mnks) leads to the release and translation of mRNAs of specific oncogenic proteins. In recent years, the efforts made by the pharmaceutical industry to develop novel chemical skeletons to create potent and selective Mnk inhibitors have been fruitful. The pyridone-aminal scaffold has been utilized to generate several series of Mnk inhibitors presented in multiple patent applications and research articles. Tomivosertib (eFT508) is one of the molecules with such scaffold. It is one of the first two Mnk inhibitors that entered clinical trials, and has displayed momentous activity against several solid and hematological cancers. The present compilation provides a succinct review of the current state of development of pyridone-aminal-derived Mnk inhibitors through the analysis of relevant patent applications filed in the last 5 years.

scholarly journals The Mitogen-Activated Protein Kinase Signal-Integrating Kinase Mnk2 Is a Eukaryotic Initiation Factor 4E Kinase with High Levels of Basal Activity in Mammalian Cells

2001 ◽  
Vol 21 (3) ◽  
pp. 743-754 ◽  
Author(s):  
Gert C. Scheper ◽  
Nick A. Morrice ◽  
Miranda Kleijn ◽  
Christopher G. Proud
Keyword(s):  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
3T3 Cells ◽  
Mapk Pathways ◽  
Eukaryotic Initiation Factor 4E ◽  
Mitogen Activated Protein ◽  
Swiss 3T3

ABSTRACT The cap-binding translation initiation factor eukaryotic initiation factor 4E (eIF4E) is phosphorylated in vivo at Ser209 in response to a variety of stimuli. In this paper, we show that the mitogen-activated protein kinase (MAPK) signal-integrating kinase Mnk2 phosphorylates eIF4E at this residue. Mnk2 binds to the scaffolding protein eIF4G, and overexpression of Mnk2 results in increased phosphorylation of endogenous eIF4E, showing that it can act as an eIF4E kinase in vivo. We have identified eight phosphorylation sites in Mnk2, of which at least three potential MAPK sites are likely to be essential for Mnk2 activity. In contrast to that of Mnk1, the activity of overexpressed Mnk2 is high under control conditions and could only be reduced substantially by a combination of PD98059 and SB203580, while the activity of endogenous Mnk2 in Swiss 3T3 cells was hardly affected upon treatment with these inhibitors. These compounds did not abolish phosphorylation of eIF4E, implying that Mnk2 may mediate phosphorylation of eIF4E in Swiss 3T3 cells. In vitro phosphorylation studies show that Mnk2 is a significantly better substrate than Mnk1 for extracellular signal-regulated kinase 2 (ERK2), p38MAPKα, and p38MAPKβ. Therefore, the high levels of activity of Mnk2 under several conditions may be explained by efficient activation of Mnk2 by low levels of activity of the upstream kinases. Interestingly, we found that the association of both Mnk1 and Mnk2 with eIF4G increased upon inhibition of the MAPK pathways while activation of ERK resulted in decreased binding to eIF4G. This might reflect a mechanism to ensure rapid, but transient, phosphorylation of eIF4E upon stimulation of the MAPK pathways.

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