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Dysregulated hippo pathway has been implicated in tumor progression and therapeutic resistance of various cancers through effector transcriptional coactivators YAP/TAZ. TEA domain transcription factors (TEAD1–4) exert activity of YAP/TAZ and have emerged as important anti-cancer targets. Several co-crystal structures complexed with flufenamic acid and related molecules in the central pocket of YAP binding domain (YBD) of TEADs are available from the public domain. While structural diversity of inhibitors exists, they share similar binding poses within the TEAD central pocket and are highly lipophilic with poor aqueous solubility. Herein, we use structure-based and rational drug design to create compounds with improved drug-like properties, introducing polarity to optimize physicochemical properties. The culmination of this work resulted in the discovery of (R)-3-(5-(1-methyl-3-((4-(trifluoromethyl)phenyl)amino)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)-3-vinylpyrrolidin-2-one (16), a reversible TEAD inhibitor exhibiting excellent oral mouse PK, dose-dependent increases in plasma exposure, and dose-dependent tumor regression of YAP-dependent H266 human mesothelioma xenograft model in mice with good tolerability.
Cao et al. (Thu,) studied this question.