- Design of Development Candidate eFT226, a First in Class Inhibitor of Eukaryotic Initiation Factor 4A RNA Helicase
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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.
- Ernst, Justin T.,Thompson, Peggy A.,Nilewski, Christian,Sprengeler, Paul A.,Sperry, Samuel,Packard, Garrick,Michels, Theodore,Xiang, Alan,Tran, Chinh,Wegerski, Christopher J.,Eam, Boreth,Young, Nathan P.,Fish, Sarah,Chen, Joan,Howard, Haleigh,Staunton, Jocelyn,Molter, Jolene,Clarine, Jeff,Nevarez, Andres,Chiang, Gary G.,Appleman, Jim R.,Webster, Kevin R.,Reich, Siegfried H.
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Read Online
- Phase transfer catalysis extends the scope of the Algar-Flynn-Oyamada synthesis of 3-Hydroxyflavones
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The Algar-Flynn-Oyamada reaction is the classical method to synthesize 3-hydroxyflavones from chalcones. Despite its relative simplicity, the reaction has several drawbacks including variable and often low product yields. We have found that phase transfer
- Nhu, Duong,Hawkins, Bill C.,Burns, Christopher J.
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p. 1102 - 1107
(2016/01/15)
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- Synthesis and biological evaluation of flavan-3-ol derivatives as positive modulators of GABAA receptors
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We herein describe the synthesis and positive modulatory activities of a small library of flavan-3-ol derivatives on α1β2γ2L GABAA receptors. Structure-activity relationships of various substituents on the A, B
- Mewett, Kenneth N.,Fernandez, Sebastian P.,Pasricha, Anmol K.,Pong, Alice,Devenish, Steven O.,Hibbs, David E.,Chebib, Mary,Johnston, Graham A.R.,Hanrahan, Jane R.
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experimental part
p. 7156 - 7173
(2010/03/04)
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- Synthesis of a library of glycosylated flavonols
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Flavonols are an important class of natural products isolated from plants. Some glycosylated flavonols showed very interesting biological activities. A library of flavonols has been made through Algar-Flynn-Oyamada reaction from 2′-hydroxyacetophenones an
- Li, Zhitao,Ngojeh, George,DeWitt, Paul,Zheng, Zhi,Chen, Min,Lainhart, Brendan,Li, Vincent,Felpo, Peter
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scheme or table
p. 7243 - 7245
(2009/04/11)
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- Synthesis and inhibitory activity against COX-2 catalyzed prostaglandin production of chrysin derivatives
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A series of chrysin derivatives were prepared and evaluated for their inhibitory activities of cyclooxygenase-2 catalyzed prostaglandin production. Chrysin derivatives were prepared from 2-hydroxyacetophenone, 2,4-dihydroxyacetophenone and 2,6-dihydroxyacetophenone in 2 to 4 steps, respectively. Methxoylated chrysin derivatives were converted to the corresponding hydroxylated chrysin derivatives by the reaction with BBr 3 in good yields. The inhibitory activity of the chrysin derivatives against prostaglandin production from lipopolysaccharide-treated RAW 264.7 cells was measured. We found that chrysin derivatives with 3′,4′- dichloro substituents (5e, 6e and 7e) exhibited good inhibitory activity of prostaglandin production.
- Dao, Tran Thanh,Chi, Yeon Sook,Kim, Jeongsoo,Kim, Hyun Pyo,Kim, Sanghee,Park, Haeil
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p. 1165 - 1167
(2007/10/03)
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