Dysregulated translation of specific mRNAs is an important driver of uncontrolled growth, immune evasion and metastasis in many types of cancer. eIF4A (eukaryotic initiation factor 4A), an ATP-dependent DEAD-box RNA helicase and a key component of the eIF4F complex, plays a crucial role in translational regulation of several oncogenes, rendering it a promising therapeutic target for the treatment of cancer. Flavagline natural products have been shown to inhibit eIF4A by RNA-sequence specific formation of a stabilized eIF4A/RNA/flavagline ternary complex; however, these compounds generally display suboptimal drug-like properties. This presentation describes the design of and physicochemical property optimization in novel flavagline cores to support intravenous delivery, culminating in clinical candidate eIF4A inhibitor eFT226.

Design of clinical candidate eFT226, a first-in-class inhibitor of the RNA helicase eIF4A

2019 Spring National Meeting

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