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

SummaryIn 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 take n 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 toN7-(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 cellu lar 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-neoplas tic treatment gemcitabine currently used in NSCLC therapy.
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research