Progress with YAP/TAZ-TEAD inhibitors: a patent review (2018-present)

ABSTRACT

Introduction

The Hippo pathway represents a new opportunity for the treatment of cancer. Overexpression of Yes-associated protein (YAP) or transcriptional coactivator with PDZ-binding motif (TAZ) or TEAD has been demonstrated in cancers and YAP mediates resistance to cancer drugs. Since 2018, the potential of this pathway has been illustrated by numerous articles and patents and the first drugs entering in clinical trial phase 1.

Areas covered

This review is limited to published patent applications that have disclosed direct small-molecule inhibitors of the YAP/TAZ–TEAD interaction.

Expert opinion

The YAP/TAZ–TEAD transcriptional complex is a promising target for the treatment of cancer. Approximately 30 international patents (used database: Sci-finder, query: TEAD; documents: patents; period: from 2017-January 2022) that disclose TEAD transcriptional inhibitors have been filled since 2018. The mechanism of action is not always described in the patents, we can divide the drugs into three different categories: (i) external TEAD ligands; (ii) non-covalent TEAD ligands of the palmitate pocket; (iii) covalent TEAD ligands, which bind into the palmitate pocket. The first molecules in clinical trial phase 1 are non-covalent TEAD ligands. The selective TEAD ligand have also been patented, published and selectivity could be of great interest for personalized medicine.

KEYWORDS:

• Transcriptional factors TEAD
• hippo pathway
• selectivity
• cancers
• YAP/TAZ
• NF2-deficiency

Article highlights

• A review of published patent applications (2018-January 2022) reporting small molecule YAP/TAZ-TEAD inhibitors from academics and pharmaceutical companies.

• After academics and biotech companies, big pharmas join the dance of patent applications.

• Three molecules entered in phase 1 clinical trial in 2021 for mesothelioma treatment.

• First selective ligands of TEAD were patented.

Author contributions

B Zagiel and P Cotelle collected, analyzed and abstracted the patents. B Zagiel, P Melnyk, and P Cotelle wrote and revised the article.

Declaration of interest

The authors have no 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 work was financially supported by the Ministère de l’Enseignement Supérieur, de la Recherche et de l’Innovation, the University of Lille and INSERM.