Degradation of the TEAD·YAP/TAZ Transcription Factor Complex by Heterobifunctional Small Molecules That Bind to the TEAD Allosteric Lipid Pocket.

Central kinases of the Hippo tumor suppressor pathway phosphorylate the transcriptional coactivators YAP and TAZ to sequester them in the cytoplasm. In cancer, Hippo pathway kinases have reduced activity, leading to translocation of YAP and TAZ into the nucleus, where they engage TEADs and other transcription factors. Here, we explore whether heterobifunctional small molecules that bind to the TEAD allosteric lipid-binding pocket can degrade the TEAD·YAP/TAZ complex. We design and synthesize heterobifunctional molecules that consist of flufenamic acid analogs that bind to the allosteric TEAD lipid pocket, a long and flexible linker, and thalidomide to engage E3 ubiquitin ligase component cereblon. Proteasomal degradation of TEAD, YAP, and TAZ for the carboxylic acid compounds was modest, but methyl ester analogs led to substantial degradation of these proteins in cancer cells. This work provides a strategy for depletion of YAP and TAZ and for exploration of their TEAD-dependent and TEAD-independent activities