Back to Search Start Over

Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase.

Authors :
Ernst JT
Thompson PA
Nilewski C
Sprengeler PA
Sperry S
Packard G
Michels T
Xiang A
Tran C
Wegerski CJ
Eam B
Young NP
Fish S
Chen J
Howard H
Staunton J
Molter J
Clarine J
Nevarez A
Chiang GG
Appleman JR
Webster KR
Reich SH
Source :
Journal of medicinal chemistry [J Med Chem] 2020 Jun 11; Vol. 63 (11), pp. 5879-5955. Date of Electronic Publication: 2020 May 29.
Publication Year :
2020

Abstract

Dysregulation of protein translation is a key driver for the pathogenesis of many cancers. Eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, is a critical component of the eIF4F complex, which regulates cap-dependent protein synthesis. The flavagline class of natural products ( i.e. , rocaglamide A) has been shown to inhibit protein synthesis by stabilizing a translation-incompetent complex for select messenger RNAs (mRNAs) with eIF4A. Despite showing promising anticancer phenotypes, the development of flavagline derivatives as therapeutic agents has been hampered because of poor drug-like properties as well as synthetic complexity. A focused effort was undertaken utilizing a ligand-based design strategy to identify a chemotype with optimized physicochemical properties. Also, detailed mechanistic studies were undertaken to further elucidate mRNA sequence selectivity, key regulated target genes, and the associated antitumor phenotype. This work led to the design of eFT226 (Zotatifin), a compound with excellent physicochemical properties and significant antitumor activity that supports clinical development.

Details

Language :
English
ISSN :
1520-4804
Volume :
63
Issue :
11
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
32470302
Full Text :
https://doi.org/10.1021/acs.jmedchem.0c00182