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 is known to mediate 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 The present 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 thirty 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 although their exact structures is not known. The selective TEAD ligand have also been patented, published and selectivity could be of great interest for personalized medicine.