Hippo pathway inhibition by blocking the YAP/TAZ–TEAD interface: a patent review

ABSTRACT

Introduction: The Hippo pathway represents a new and intriguing opportunity for the treatment of cancer. Activation or overexpression of Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ) has been shown to lead to cell transformation and tumor development. To date, no small molecule compounds targeting this pathway have progressed to the clinic, illustrating both its potential and its infancy.

Areas covered: The present review seeks to summarize published patent applications from assignee companies that have disclosed direct small molecule inhibitors of the YAP/TAZ–transcriptional enhanced associate domain (TEAD) interaction.

Expert opinion: The Hippo pathway, and specifically the YAP/TAZ–TEAD transcriptional complex, has been shown to be a promising target for the treatment of cancer. However, reports in the area of small molecules targeting the YAP/TAZ–TEAD transcriptional activation complex are few and far between, with only two published patent applications that disclose compounds with moderate levels of pathway inhibition. Interestingly, the YAP/TAZ–TEAD complex can be disrupted through two very different mechanisms, one of which is direct inhibition at either the Ω-loop or the α-helix of the YAP–TEAD binding interface. Both YAP protein segments have been shown to be important to TEAD binding. Alternatively, it has been reported that allosteric inhibition might be accomplished by binding the TEAD palmitoylation pocket, thus disrupting YAP binding and also native protein stabilization. The advantages and liabilities of disrupting the YAP/TAZ–TEAD complex through these two distinct mechanisms have yet to be fully elucidated, and it remains unclear which approach, if any, will generate the first clinical stage inhibitor of the Hippo pathway.

KEYWORDS:

• Hippo pathway
• YAP
• TEAD
• TAZ

Article highlights

• A review of published patent applications reporting small molecule YAP–TEAD inhibitors from assignee companies.

• A published patent application from Inventiva has shown compounds that directly inhibit the YAP–TEAD interaction at sub-100 nM levels. These compounds were derived from NMR and fragment screens.

• A report from Massachusetts General Hospital that illustrates a different approach to the target, specifically inhibitors of auto-palmitoylation that target the central pocket of TEADs.

This box summarizes key points contained in the article.

Acknowledgments

We gratefully acknowledge Anwesha Dey and Christian Cunningham for helpful discussions. Additionally, we thank Cameron Noland for generating Figure 2.

Declaration of interest

The authors are employees of Genentech Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Genentech Inc.