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
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!