Leveraging Hot Spots of TEAD–Coregulator Interactions in the Design of Direct Small Molecule Protein-Protein Interaction Disruptors Targeting Hippo Pathway Signaling

The Hippo signaling pathway is a highly conserved pathway that plays important roles in the regulation of cell proliferation and apoptosis. Transcription factors TEAD1-4 and transcriptional coregulators YAP/TAZ are the downstream effectors of the Hippo pathway and can modulate Hippo biology. Dysregulation of this pathway is implicated in tumorigenesis and acquired resistance to therapies. The emerging importance of YAP/TAZ-TEAD interaction in cancer development makes it a potential therapeutic target. In the past decade, disrupting YAP/TAZ-TEAD interaction as an effective approach for cancer treatment has achieved great progress. This approach followed a trajectory wherein peptidomimetic YAP–TEAD protein-protein interaction disruptors (PPIDs) were first designed, followed by the discovery of allosteric small molecule PPIDs, and currently, the development of direct small molecule PPIDs. YAP and TEAD form three interaction interfaces. Interfaces 2 and 3 are amenable for direct PPID design. One direct YAP–TEAD PPID (IAG933) that targets interface 3 has entered a clinical trial in 2021. However, in general, strategically designing effective small molecules PPIDs targeting TEAD interfaces 2 and 3 has been challenging compared with allosteric inhibitor development. This review focuses on the development of direct surface disruptors and discusses the challenges and opportunities for developing potent YAP/TAZ-TEAD inhibitors for the treatment of cancer.