Fisher, M.; Fletcher, A.; Hamby, C. J.; Miles, J. T.; Greger, L.; Owens, D. D.; Davies, C. T.; Bisetto, S.; MacGregor, P.; Azevedo, A.; Drouhin, P.; Pass, M.; Brown, G. A.; Modis, L. K.; Carrara, M.

TEAD transcription factors are emerging oncology targets due to their function as key effectors of the Hippo signalling pathway, which is frequently dysregulated in cancer. Here, we report the discovery and development of potent, deep, and rapid-acting TEAD Targeted Glue degraders that leverage an aldehyde-mediated degron mechanism. Our compounds demonstrate exceptional on-pathway selectivity profiles and exhibit the expected Hippo signalling modulation. Mechanistically, we demonstrate that amine-based TEAD degrader scaffolds undergo extracellular conversion to the active aldehyde species, which mediate covalent engagement of FBXO22 C326, triggering TEAD proteasomal degradation. The degraders identified were able to be rationally and systematically optimised for both degradation potency and kinetics, achieving enhanced degradation profiles compared to previously reported FBXO22-targeting approaches, establishing design principles for this degrader class. Our findings highlight strategies for the structure activity relationship (SAR) and rational optimization of aldehyde-mediated degrons to generate novel precision molecular glue degraders against TEAD, a high value oncology target.