Design, synthesis and evaluation of analogs of initiation factor 4E (eIF4E) cap-binding antagonist Bn⁷-GMP

Aberrant regulation of cap-dependent translation has been frequently observed in the development of cancer. Association of the cap-binding protein eIF4E with N⁷-methylated guanosine capped mRNA is the rate limiting step governing translation initiation; and therefore represents an attractive process for cancer drug discovery. Previously, replacement of the 7-Me group of the Me⁷-guanosine monophosphate with a benzyl group has been found to increase binding affinity to eIF4E. Recent X-ray crystallographic studies have revealed that the cap-binding pocket undergoes a unique structural change in order to accommodate the benzyl group. To explore the structure-activity relationships governing the affinity of N⁷-benzylated guanosine monophosphate (Bn⁷-GMP) for eIF4E, we virtually screened a library of 80 Bn⁷-GMP analogs utilizing CombiGlide as implemented in Schrodinger^®. A subset library of substituted Bn⁷-GMP analogs was synthesized and their dissociation constants (K_d) were determined. Due to the poor correlation between docking/scoring results and experimental binding affinities, three-dimensional quantitative structure-activity relationship (3D-QSAR) calculations were performed. Two highly predictive and self-consistent CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were derived and optimized. These models may be useful for the future design of eIF4E cap-binding antagonists.