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

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.

蛋白质翻译的失调是众多癌症发病机制的关键驱动力。真核起始因子4A（eIF4A），一种依赖于ATP的DEAD-box RNA解旋酶，是eIF4F复合体的关键组成部分，该复合体调控帽依赖性蛋白质合成。天然产物中黄酮苷类（例如，rocaglamide A）被发现可以通过稳定与eIF4A结合的选择性翻译无能复合物来抑制蛋白质合成。尽管黄酮苷衍生物显示出有希望的抗癌表型，但由于其药代动力学性质不佳以及合成复杂性，其作为治疗剂的开发受到了阻碍。为此，我们采取了一种基于配体的设计策略，致力于识别具有优化物理化学性质的化学类型。此外，还进行了详细的作用机制研究，以进一步阐明mRNA序列选择性、关键调控靶基因及其相关的抗肿瘤表型。这项工作导致了eFT226（Zotatifin）的设计，该化合物具有卓越的物理化学性质和显著的抗肿瘤活性，为临床开发提供了支持。