Identification of a Quinone Derivative as a YAP/TEAD Activity Modulator from a Repurposing Library.

Matteo Santucci,Gaia Gozzi,Stefania Ferrari,Elisa Uliassi,Laura Scalvini,Lorena Losi,Maria Laura Bolognesi,Gian Marco Elisi,Maria Paola Costi,Angela Lauriola,Domenico D’Arca,Gaetano Marverti,Marco Mor,Lorenzo Tagliazucchi

doi:10.3390/pharmaceutics14020391

Abstract

The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27-member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect. In a secondary luciferase-based assay, only seven compounds confirmed their specific involvement in TEAD activity. IA5 bearing a p-quinoid structure reduced the cytoplasmic level of phosphorylated YAP and the YAP–TEAD complex transcriptional activity and reduced cancer cell growth. IA5 is a promising hit compound for TEAD activity modulator development.

Highlights

The library size was restricted to lead-like compounds based on: (i) chemical diversity, (ii) potential connection established by the compounds’ target with Yes1-associated protein (YAP)-transcriptional enhanced associate domain (TEAD) and the Hippo pathway activity, and (iii) structural features suitable for protein–protein interactions (PPIs) inhibition. This allowed us to provide a reasonable coverage of chemical space, and high-quality starting points for further optimization studies
Since the YAP–TEAD complex is an interesting target in cancer, modulating the interaction of YAP/transcriptional co-activator with PDZ-binding motif (TAZ) with transcriptional factor, TEAD, may be an effective strategy for cancer therapy [11]
We included VP, the first small molecule reported as a YAP-TEAD disrupter [17,76]

Summary

Introduction

The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. The YAP and TAZ functional activity is implicated in the tumorigenesis of various cancers, including breast [1,2], colon [3], and lung [4] In tumors, these proteins can reprogram cancer cells into cancer stem cells and incite tumor initiation, progression, and metastasis [5,6,7].

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Results

Conclusion