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eFT226 (zotatifin) is a beautiful natural product-derived molecule that inhibits the RNA helicase eIF4A by forming a ternary complex between it, eIF4A, and polypurine RNA. Interestingly, the stability of the ternary complex depends on the RNA sequence bound to eIF4A, with greatest activity for AGAGAG-based complexes. The molecule demonstrates significant activity in tumor xenografts with once weekly dosing of as little as 1 mg/kg compound IV and entered clinical development last year. Chemists will appreciate the neat photocycloaddition/ketol-rearrangement used to synthesize the compound. I’m looking forward to learning how this was scaled up for clinical development!