Global Proteomics to assess specificity of IAP recruiting TEAD1 degrader

TEAD transcription factors (TEAD1-4) are the downstream most effectors of Hippo pathway, that controls organ development and tissue homeostasis. TEAD proteins form a transcriptional complex with co-activators YAP-TAZ to transcribe genes that regulate cell proliferation/apoptosis. Since Hippo pathway dysregulation is common in cancer phenotypes, inhibiting / degrading TEAD and its subsequent transcriptional activity is an attractive therapeutic strategy. We exploited targeted protein degradation approach using IAP proteins as E3 ligases to target TEAD1 and develop a potent isoform specific degrader. In this study we describe development and functional profiling of hits from three such series of IAP recruiting degraders (IPDs). We also report a detailed toolkit using structural, biophysical and cellular approaches to study IAP recruiting degraders that target the lipid pocket of TEAD proteins. To assess degradation and isoform specificity of our most potent hit XB2 A538, we also analysed global proteomic changes in mesothelioma model cell line NCI-H2052, treated for 16 hours with TEAD IPD A538, matched IAP negative control, TEAD negative control and DMSO, reported in data deposited here.