Targeted degradation of specific TEAD paralogs by small molecule degraders.

The transcription factors, TEAD1-4 together with their co-activator YAP/TAZ function as key downstream effectors of the Hippo pathway. Hyperactivation of TEAD-YAP/TAZ activity is observed in many human cancers. TEAD1-4 possess distinct physiological and pathological functions, with conserved sequences and structures. Targeting specific isoforms within TEAD1-4 can serve as valuable chemical probes for investigating TEAD-related functions in both development and diseases. We report the TEAD-targeting proteolysis targeting chimera (PROTAC), , which achieves effective and specific targeting of TEAD1 and TEAD3 at low nanomolar doses while weakly degrading TEAD2 and TEAD4 at higher doses. Proteomic analysis of >6000 proteins confirmed their highly selective TEAD1 and TEAD3 degradation. Consistently, can suppress the proliferation of YAP-dependent NCI-H226 mesothelioma cells. Mechanistic exploration revealed that both CRBN and proteasome systems are involved in the TEAD degradation induced by . Moreover, RNA-seq and Gene Set Enrichment Analysis (GSEA) revealed that the YAP signature genes such as CTGF, CYR61, and ANKRD1 are significantly downregulated by treatment. Overall, serves as a valuable chemical tool for unraveling the intricate biological roles of TEAD1 and TEAD3 and holds the potential as a lead compound for developing targeted therapy for TEAD1/3-driven pathologies.