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Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase.
- 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.
- Subjects :
- Animals
Benzofurans pharmacokinetics
Benzofurans therapeutic use
Binding Sites
Breast Neoplasms drug therapy
Breast Neoplasms pathology
Cell Line, Tumor
Crystallography, X-Ray
Eukaryotic Initiation Factor-4A genetics
Eukaryotic Initiation Factor-4A metabolism
Female
Half-Life
Humans
Ligands
Mice
Mice, Nude
Molecular Dynamics Simulation
Mutagenesis, Site-Directed
Protein Structure, Tertiary
RNA, Messenger chemistry
RNA, Messenger metabolism
Rats
Structure-Activity Relationship
Benzofurans chemistry
Drug Design
Eukaryotic Initiation Factor-4A antagonists & inhibitors
Subjects
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