Expanding the toolbox to develop IAP-based degraders of TEAD transcription factors.

The TEAD transcription factors (TEAD1-4) are critical effectors of the Hippo pathway, forming active nuclear complexes with transcriptional co-activators YAP/TAZ to regulate cell growth/apoptosis pathways and control fundamental processes such as organ size. Frequent dysregulation of the Hippo pathway in cancer and the presence of druggable binding sites on TEADs make them attractive targets for development of small molecule inhibitors and degraders. Here, we identify and mechanistically characterize three unique series of bifunctional degraders that target TEAD1 via a lipid pocket and recruit different members of the Inhibitor of Apoptosis proteins (IAPs) family to effect degradation of TEAD1. We provide a detailed toolkit for structural, biophysical and cellular profiling, including the development of a cellular target engagement assay for the lipid pocket of TEAD1 and an IAP/TEAD1 ternary complex formation assay. Our study therefore provides essential resources for detailed characterization of IAP-recruiting degraders and important tools and learnings for bifunctional degraders targeted to the lipid pocket of TEADs.