An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid

Wnt/beta-catenin signalling controls development and tissue homeostasis. Moreover, activated beta-catenin can be oncogenic and, notably, drives colorectal cancer. Inhibiting oncogenic beta-catenin has proven a formidable challenge. Here we design a screen for small-molecule inhibitors of beta-catenin's binding to its cofactor BCL9, and discover five related natural compounds, including carnosic acid from rosemary, which attenuates transcriptional beta-catenin outputs in colorectal cancer cells. Evidence from NMR and analytical ultracentrifugation demonstrates that the carnosic acid response requires an intrinsically labile alpha-helix (H1) amino-terminally abutting the BCL9-binding site in beta-catenin. Similarly, in colorectal cancer cells with hyperactive beta-catenin signalling, carnosic acid targets predominantly the transcriptionally active ('oncogenic') form of beta-catenin for proteasomal degradation in an H1-dependent manner. Hence, H1 is an 'Achilles' Heel' of beta-catenin, which can be exploited for destabilization of oncogenic beta-catenin by small molecules, providing proof-of-principle for a new strategy for developing direct inhibitors of oncogenic beta-catenin.