4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer
- PDF / 870,640 Bytes
- 8 Pages / 595.276 x 790.866 pts Page_size
- 53 Downloads / 168 Views
PRECLINICAL STUDIES
4Ei-10 interdiction of oncogenic cap-mediated translation as therapy for non-small cell lung cancer Blake A. Jacobson 1 & Zeeshan Ahmad 1 & Sierra Chen 2 & Gabriella Waldusky 1 & Maxwell Dillenburg 3 & Emilia Stoian 4 & Daniel A. Cambron 5 & Anil J. Patel 1 & Manish R. Patel 1 & Carston R. Wagner 3 & Robert A. Kratzke 1,6 Received: 6 October 2020 / Accepted: 18 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary 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. Keywords 4Ei-10 . ProTide . eIF4E . eIF4G . Cap-dependent translation . Non-small cell lung cancer
Introduction The heterotrimeric eIF4Fcomplex, necessary for translation initiation, consists of the RNA helicase eIF4A, the scaffolding protein eIF4G, and the cap-binding protein eIF4E. Nearly all eukaryotic mRNAs require the presence of a 7methylgaunosine (Me7GTP) cap structure positioned at their 5′ end. eIF4E binds to the cap while eIF4G stabilizes the capmRNA interaction while RNA helicase eIF4A unwinds the * Robert A. Kratzke [email protected] 1
Department of Medicine, University of Minnesota, Minneapolis, MN, USA
2
Wayzata High School, Plymouth, MN, USA
3
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA
4
St. Olaf College, Northfield, MN, USA
5
Florida International University, Miami, FL, USA
6
Division of Heme-Onc-Transplant, University of Minnesota Medical School, MMC 480, 420 Delaware St SE, Minneapolis, MN 55455, USA
secondary structure of the mRNA permitting access for the 43S pre-initiation complex to scan for the AUG start codon [1]. eIF4E is believed to be the rate-limiting factor for the assembly of the eIF4F complex [2]. During normal growth conditions active (hypophosphorylated) eIF4E binding proteins (4E-BPs) negatively control translation initiation by binding to eIF4E at the same mutually exclusive site as eIF4G, thereby blocking the binding of
Data Loading...
