A cell-based screening approach identified an azaindole-based hit, optimized to the pan-TEAD inhibitor MSC-2723, which demonstrated monotherapy effects in vivo. Structure-derived scaffold modifications led to the lactam-based TEAD1,2,4 inhibitor MSC-9643, which exhibited convincing synergism with an approved drug in vivo. Scaffold tuning resulted in the brain-penetrant inhibitor MSC-4070. Proton/deuterium exchange experiments with a fragment derived TEAD1 selective inhibitor revealed how TEAD P-site binding compounds interfere with the formation of an active YAP/TAZ-TEAD transcription complex. Together with MD simulations a working hypothesis is developed how TEAD selectivity impacts the benefit/risk ratio.