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

Bin Zhao; Ajaybabu V Pobbati; Brian P Rubin; Shaun Stauffer

doi:10.3390/ph16040583

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

Pharmaceuticals (Basel). 2023 Apr 13;16(4):583. doi: 10.3390/ph16040583.

Authors

Bin Zhao^{1

2}, Ajaybabu V Pobbati^{2

3}, Brian P Rubin^{3

4}, Shaun Stauffer^{1

2}

Affiliations

¹ Cleveland Clinic Center for Therapeutics Discovery, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA.
² Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
³ Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
⁴ Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

Abstract

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.

Keywords: Hippo pathway; TEAD; VGLL; YAP; protein-protein interaction; transcription.

Publication types

Review

Grants and funding

This study was supported from the Cleveland Clinic/Lerner Research Institute Department of Cancer Biology (Multi-PI pilot grant; B.P.R. and S.S.), the Margie & Robert E. Petersen Foundation (B.P.R.), the Epithelioid Hemangioendothelioma Foundation (B.P.R.), the EHE Rare Cancer Charity UK (B.P.R.), and the EHE Rare Cancer Charity Australia (B.P.R.).