Selective eIF4F translation regulators for cancer therapy

Cancer is a challenging disease with limited therapeutic options and high worldwide mortality rates. Dysregulation of mRNA translation of oncogenes that enhance proliferation, survival, and resistance to apoptosis is crucial for tumor development. Therefore, inhibiting components of the protein translation machinery (the eIF4F-complex), a central downstream node of oncogenic pathways including PI3K/mTOR and KRAS, would be particularly beneficial for cancer treatment.Small-molecule inhibitors targeting the translation machinery hold considerable potential for overcoming intra tumor heterogeneity of the genetic makeup of cancer cells. Targeting eIF4F also elicits potent antitumor immune-mediated effects via PD-L1 downregulation. The benefits and promise of targeting the eIF4F complex has thus attracted the interest and efforts of both the pharma and biotech worlds. Boston University researchers have developed efficient synthetic methods to create novel derivatives of the rocaglamide family of natural products, with high potency (sub nM) and selectivity for translation machinery components. Studies at McGill identified compounds that effectively sensitized myr-Akt/Eμ-Myclymphoma tumors in vivo to the effects of doxorubicin. Targeting the eIF4F complex creates an opportunity for a single anticancer therapeutic agent or combination agents, with a wide range of applications in solid or hematological cancers. Thomas J McMurry tmcmurry@bu.edu 617-358-4550