molecules of the month

eFT226 (zotatifin)

first-in-class eIF4A RNA helicase inhibitor

in clinical dev. for solid tumors (Ph. I, IV QW)

from optimization of a natural product

J. Med. Chem., May 29, 2020

eFFECTOR Therapeutics, San Diego, CA

1 min read

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!

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