Targeted degradation of specific TEAD paralogs by small molecule degraders

Abstract

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), HC278, 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, HC278 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 HC278. 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 HC278 treatment. Overall, HC278 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.