Identification of a First-in-Class Small Molecule Inhibitor of the eIF4E-RBM38 Complex that Enhances wild-type p53 Protein Translation for Tumor Growth Suppression

Abstract eIF4E, an mRNA cap-binding protein, is necessary for cap-dependent translation. Overexpression of eIF4E is known to promote cancer development by preferentially translating a group of oncogenic mRNAs. Thus, 4EGI-1, a disruptor of eIF4E-eIF4G interaction, was developed to inhibit oncoprotein expression for cancer therapy. Interestingly, RBM38, an RNA-binding protein, interacts with eIF4E on p53 mRNA, prevents eIF4E from binding to p53 mRNA cap, and inhibits p53 expression. Thus, Pep8, an eight amino acid peptide derived from RBM38, was developed to disrupt the eIF4E-RBM38 complex, leading to increased p53 expression and decreased tumor cell growth. Herein, we have developed a first-in-class small molecule compound 094, which interacts with eIF4E via the same pocket as does Pep8, dissociates RBM38 from eIF4E, and enhances p53 translation in RBM38- and eIF4E-dependent manners. Structure-activity relationship (SAR) studies identified that both the fluorobenzene and ethyl benzamide are necessary for compound 094 to interact with eIF4E. Further, we showed that compound 094 is capable of suppressing 3D tumor spheroid growth in RBM38- and p53-dependent manners. Additionally, we found that compound 094 cooperates with chemotherapeutic agent doxorubicin and eIF4E inhibitor 4EGI-1 to suppress tumor cell growth. Collectively, we showed that two distinct approaches can be used together to target eIF4E for cancer therapy by enhancing wild-type p53 expression (094), and by suppressing oncoprotein expression (4EGI-1).