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

J Med Chem. 2020 Jun 11;63(11):5879-5955. doi: 10.1021/acs.jmedchem.0c00182.

Justin T Ernst ¹, Peggy A Thompson ², Christian Nilewski ³, Paul A Sprengeler ², Samuel Sperry ², Garrick Packard ¹, Theodore Michels ⁴, Alan Xiang ⁵, Chinh Tran ², Christopher J Wegerski ², Boreth Eam ⁶, Nathan P Young ⁷, Sarah Fish ⁸, Joan Chen ², Haleigh Howard ⁹, Jocelyn Staunton ², Jolene Molter ², Jeff Clarine ⁴, Andres Nevarez ¹⁰, Gary G Chiang ², Jim R Appleman ¹¹, Kevin R Webster ¹², Siegfried H Reich ²

Affiliations

1 Inception Therapeutics, 6175 Nancy Ridge Drive, San Diego, California 92121, United States.
2 eFFECTOR Therapeutics, 11180 Roselle Street, San Diego, California 92121, United States.
3 Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
4 GossamerBio., 3013 Science Park Road, San Diego, California 92121, United States.
5 WuXi AppTec, 6114 Nancy Ridge Drive, San Diego, California 92121, United States.
6 Calporta Therapeutics, 11099 North Torrey Poines Rd., La Jolla, California 92037, United States.
7 Casma Therapeutics, 400 Technology Square, Cambridge, California 02139, United States.
8 Plexium, Inc., 11585 Sorrento Valley Rd., San Diego, California 92121, United States.
9 Providence Portland Medical Center, 4805 NE Glisan Street, Portland, Oregon 97213, United States.
10 Escient Pharmaceuticals, 10578 Science Center Dr., San Diego, California 92121, United States.
11 Primmune Therapeutics, 3210 Merryfield Row, San Diego, California 92121, United States.
12 Frontier Medicines Corp., 151 Oyster Point Blvd., South San Francisco, California 94080, United States.

PMID: 32470302 DOI: 10.1021/acs.jmedchem.0c00182

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.

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