4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer

Blake A. Jacobson; Zeeshan Ahmad; Sierra Chen; Gabriella Waldusky; Maxwell Dillenburg; Emilia Stoian; Daniel A. Cambron; Anil J. Patel; Manish R. Patel; Carston R. Wagner; Robert A. Kratzke

doi:10.1007/s10637-020-01036-8

4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer

Blake A. Jacobson, Zeeshan Ahmad, Sierra Chen, Gabriella Waldusky, Maxwell Dillenburg, Emilia Stoian, Daniel A. Cambron, Anil J. Patel, Manish R. Patel, Carston R. Wagner, Robert A. Kratzke

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

In order to suppress 5′ cap-mediated translation a highly available inhibitor of the interaction between the 5’ mRNA cap and the eIF4E complex has been developed. 4Ei-10 is a member of the class of ProTide compounds and has elevated membrane permeability and is a strong active chemical antagonist for eIF4E. Once taken up by cells it is converted by anchimeric activation of the lipophilic 2-(methylthio) ethyl protecting group and after that Hint1 P-N bond cleavage to N⁷-(p-chlorophenoxyethyl) guanosine 5′-monophosphate (7-Cl-Ph-Ethyl-GMP). Using this powerful interaction, it has been demonstrated that 4Ei-10 inhibits non-small cell lung cancer (NSCLC) cell growth. In addition, treatment of NSCLC cells with 4Ei-10 results in suppression of translation and diminished expression of a cohort of cellular proteins important to maintaining the malignant phenotype and resisting apoptosis such as Bcl-2, survivin, and ornithine decarboxylase (ODC). Finally, as a result of targeting the translation of anti-apoptotic proteins, NSCLC cells are synergized to be more sensitive to the existing anti-neoplastic treatment gemcitabine currently used in NSCLC therapy.

Original language	English (US)
Pages (from-to)	636-643
Number of pages	8
Journal	Investigational New Drugs
Volume	39
Issue number	3
DOIs	https://doi.org/10.1007/s10637-020-01036-8
State	Published - 2020

Bibliographical note

Funding Information:
The work was supported by the John Skoglund Fund for Lung Cancer Research at the University of Minnesota.

Keywords

4Ei-10
Cap-dependent translation
Non-small cell lung cancer
ProTide
eIF4E
eIF4G

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s10637-020-01036-8

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title = "4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer",

abstract = "In order to suppress 5′ cap-mediated translation a highly available inhibitor of the interaction between the 5{\textquoteright} mRNA cap and the eIF4E complex has been developed. 4Ei-10 is a member of the class of ProTide compounds and has elevated membrane permeability and is a strong active chemical antagonist for eIF4E. Once taken up by cells it is converted by anchimeric activation of the lipophilic 2-(methylthio) ethyl protecting group and after that Hint1 P-N bond cleavage to N7-(p-chlorophenoxyethyl) guanosine 5′-monophosphate (7-Cl-Ph-Ethyl-GMP). Using this powerful interaction, it has been demonstrated that 4Ei-10 inhibits non-small cell lung cancer (NSCLC) cell growth. In addition, treatment of NSCLC cells with 4Ei-10 results in suppression of translation and diminished expression of a cohort of cellular proteins important to maintaining the malignant phenotype and resisting apoptosis such as Bcl-2, survivin, and ornithine decarboxylase (ODC). Finally, as a result of targeting the translation of anti-apoptotic proteins, NSCLC cells are synergized to be more sensitive to the existing anti-neoplastic treatment gemcitabine currently used in NSCLC therapy.",

keywords = "4Ei-10, Cap-dependent translation, Non-small cell lung cancer, ProTide, eIF4E, eIF4G",

author = "Jacobson, {Blake A.} and Zeeshan Ahmad and Sierra Chen and Gabriella Waldusky and Maxwell Dillenburg and Emilia Stoian and Cambron, {Daniel A.} and Patel, {Anil J.} and Patel, {Manish R.} and Wagner, {Carston R.} and Kratzke, {Robert A.}",

note = "Funding Information: The work was supported by the John Skoglund Fund for Lung Cancer Research at the University of Minnesota. ",

year = "2020",

doi = "10.1007/s10637-020-01036-8",

language = "English (US)",

volume = "39",

pages = "636--643",

journal = "Investigational New Drugs",

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T1 - 4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer

AU - Jacobson, Blake A.

AU - Ahmad, Zeeshan

AU - Chen, Sierra

AU - Waldusky, Gabriella

AU - Dillenburg, Maxwell

AU - Stoian, Emilia

AU - Cambron, Daniel A.

AU - Patel, Anil J.

AU - Patel, Manish R.

AU - Wagner, Carston R.

AU - Kratzke, Robert A.

N1 - Funding Information: The work was supported by the John Skoglund Fund for Lung Cancer Research at the University of Minnesota.

PY - 2020

Y1 - 2020

N2 - In order to suppress 5′ cap-mediated translation a highly available inhibitor of the interaction between the 5’ mRNA cap and the eIF4E complex has been developed. 4Ei-10 is a member of the class of ProTide compounds and has elevated membrane permeability and is a strong active chemical antagonist for eIF4E. Once taken up by cells it is converted by anchimeric activation of the lipophilic 2-(methylthio) ethyl protecting group and after that Hint1 P-N bond cleavage to N7-(p-chlorophenoxyethyl) guanosine 5′-monophosphate (7-Cl-Ph-Ethyl-GMP). Using this powerful interaction, it has been demonstrated that 4Ei-10 inhibits non-small cell lung cancer (NSCLC) cell growth. In addition, treatment of NSCLC cells with 4Ei-10 results in suppression of translation and diminished expression of a cohort of cellular proteins important to maintaining the malignant phenotype and resisting apoptosis such as Bcl-2, survivin, and ornithine decarboxylase (ODC). Finally, as a result of targeting the translation of anti-apoptotic proteins, NSCLC cells are synergized to be more sensitive to the existing anti-neoplastic treatment gemcitabine currently used in NSCLC therapy.

AB - In order to suppress 5′ cap-mediated translation a highly available inhibitor of the interaction between the 5’ mRNA cap and the eIF4E complex has been developed. 4Ei-10 is a member of the class of ProTide compounds and has elevated membrane permeability and is a strong active chemical antagonist for eIF4E. Once taken up by cells it is converted by anchimeric activation of the lipophilic 2-(methylthio) ethyl protecting group and after that Hint1 P-N bond cleavage to N7-(p-chlorophenoxyethyl) guanosine 5′-monophosphate (7-Cl-Ph-Ethyl-GMP). Using this powerful interaction, it has been demonstrated that 4Ei-10 inhibits non-small cell lung cancer (NSCLC) cell growth. In addition, treatment of NSCLC cells with 4Ei-10 results in suppression of translation and diminished expression of a cohort of cellular proteins important to maintaining the malignant phenotype and resisting apoptosis such as Bcl-2, survivin, and ornithine decarboxylase (ODC). Finally, as a result of targeting the translation of anti-apoptotic proteins, NSCLC cells are synergized to be more sensitive to the existing anti-neoplastic treatment gemcitabine currently used in NSCLC therapy.

KW - 4Ei-10

KW - Cap-dependent translation

KW - Non-small cell lung cancer

KW - ProTide

KW - eIF4E

KW - eIF4G

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IS - 3

ER -

4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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