Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106

ABSTRACT: The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable. The discovery and optimization of a P-site binding fragment (1) are described. Utilizing structure-based design, enhancement in target potency was engineered into the hit, capitalizing on the established X-ray structure of TEAD1. The efforts culminated in the optimized in vivo tool MSC-4106, which exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy. In close correlation to compound exposure, the time- and dose-dependent downregulation of a proximal biomarker could be shown.

Automated summary

The dysregulated Hippo pathway and hyperactivity of the YAP/TAZ-TEAD transcriptional complexes are associated with diseases like cancer. This study describes the discovery and optimization of a P-site binding fragment to target the TEAD transcription factors. The optimized in vivo tool, MSC-4106, exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy.