caa a22 4500 528785087 20190713030951.0 cr unu---uuuuu 180924s2012 xx s 000 0 eng 10.3929/ethz-b-000062260 doi 10.1038/ncomms1680 doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/62260 An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid [Elektronische Daten] [Marc De la Roche, Trevor J. Rutherford, Deepti Gupta, Dmitry B. Veprintsev, Barbara Saxty, Stefan M. Freund, Mariann Bienz] Nat Commun Open access ethresearch Wnt/β-catenin signalling controls development and tissue homeostasis. Moreover, activated β-catenin can be oncogenic and, notably, drives colorectal cancer. Inhibiting oncogenic β-catenin has proven a formidable challenge. Here we design a screen for small-molecule inhibitors of β-catenin's binding to its cofactor BCL9, and discover five related natural compounds, including carnosic acid from rosemary, which attenuates transcriptional β-catenin outputs in colorectal cancer cells. Evidence from NMR and analytical ultracentrifugation demonstrates that the carnosic acid response requires an intrinsically labile α-helix (H1) amino-terminally abutting the BCL9-binding site in β-catenin. Similarly, in colorectal cancer cells with hyperactive β-catenin signalling, carnosic acid targets predominantly the transcriptionally active ('oncogenic') form of β-catenin for proteasomal degradation in an H1-dependent manner. Hence, H1 is an 'Achilles' Heel' of β-catenin, which can be exploited for destabilization of oncogenic β-catenin by small molecules, providing proof-of-principle for a new strategy for developing direct inhibitors of oncogenic β-catenin. Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported http://creativecommons.org/licenses/by-nc-nd/3.0 ethresearch De la Roche Marc joint author Rutherford Trevor J. joint author Gupta Deepti joint author Veprintsev Dmitry B. joint author Saxty Barbara joint author Freund Stefan M. joint author Bienz Mariann joint author Nature Communications London : Nature Publishing Group 3, p. 680 2041-1723 http://hdl.handle.net/20.500.11850/62260 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/62260 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- De la Roche Marc joint author ETHRESEARCH 700 1- Rutherford Trevor J. joint author ETHRESEARCH 700 1- Gupta Deepti joint author ETHRESEARCH 700 1- Veprintsev Dmitry B. joint author ETHRESEARCH 700 1- Saxty Barbara joint author ETHRESEARCH 700 1- Freund Stefan M. joint author ETHRESEARCH 700 1- Bienz Mariann joint author ETHRESEARCH 773 0- Nature Communications London : Nature Publishing Group 3, p. 680 2041-1723 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access