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.

蛋白质翻译失调是多种癌症发病机制的关键驱动因素。真核起始因子4A（eukaryotic initiation factor 4A，eIF4A）是一类ATP依赖的DEAD盒RNA解旋酶，亦是调控帽依赖型蛋白质合成的eIF4F复合物的关键组成部分。黄镰孢菌素类（flavagline）天然产物（如罗卡酰胺A，rocaglamide A）已被证实可通过与eIF4A结合，稳定针对特定信使RNA（mRNA）的无翻译活性复合物，从而抑制蛋白质合成。尽管该类化合物展现出颇具前景的抗癌表型，但由于类药特性欠佳且合成复杂度较高，黄镰孢菌素类衍生物作为治疗药物的开发进程受到了阻碍。本研究采用基于配体的设计策略，定向筛选获得一类理化性质优化的化学型（chemotype）；此外，本研究还开展了详尽的机制研究，进一步阐明了其对mRNA序列的选择性、关键调控靶基因以及相关的抗肿瘤表型。此项研究最终成功设计得到eFT226（Zotatifin）——一种具备优异理化性质与显著抗肿瘤活性的化合物，其特性足以支持其开展临床开发。