The flavagline family of natural products is a large class of compounds characterized by their cyclopenta-benzofuran core. Many members of this family are known to possess potent antiproliferative activity in multiple cancer cell lines. Flavaglines bind to eukaryotic initiation factor 4A (eIF4A) and stabilize the mRNA-eIF4A complex, thereby inhibiting translation. While these compounds and many synthetic analogues have shown potent in vitro antiproliferative activity, progression to the clinic has been stymied by their poor physical and pharmacokinetic profile. In order to generate compounds with more drug-like properties a program aimed at improving solubility and lowering the logP of the natural products was initiated. Focus was placed on filling in the gaps in the established structure-activity relationships (SAR) of these complex molecules. A wide array of bioisosteres and structural modifications were synthesized and antiproliferative activities assayed. These efforts culminated in the discovery of eFT226, a molecule whose noteworthy characteristics include a pyridine core scaffold and a C2 aminomethyl substituent. Preclinical efficacy studies using eFT226 showed in vivo activity across multiple hematological tumor models. Clinical trials in patients with hematological and other malignancies are planned.

Synthesis of bioactive flavagline analogues as inhibitors of cap-dependent translation: Discovery of eFT226

2019 Fall National Meeting

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