Abstract 3094: Discovery of a HeliconTM peptide inhibitor of the beta-catenin-TCF interaction with in vivo activity

Wnt signaling pathway mutations leading to constitutive activation of the driver oncogene β-catenin occur in at least 20% of all human cancers, but β-catenin itself has remained undruggable by traditional modalities. In order to inhibit the activity of β-catenin, we have developed conformationally hyperstabilized α-helical peptides (Helicons) that are cellularly permeable and bind directly to β-catenin in order to block its interaction with TCF family of transcription factors. Starting with a helical peptide derived from phage display, a combination of structural biology insights and medicinal chemistry optimization improved β-catenin binding of lead peptides to picomolar affinity. Cellular permeability was achieved by modification of physical properties as well as cyclization strategies to enforce helicity and manage backbone amide bonds. Helicons show excellent pharmacokinetic profiles suitable for intermittent dosing. β-catenin targeting helicons demonstrate on-target activity and potent inhibition of Wnt-driven tumor growth in vivo. Citation Format: Brian H. White, Yaguang Si, Sarah Cappucci, Zhi Li, Jessica D. Ramirez, Charles M. Ponthier, Erica Visness, Peicheng Du, Minjung Choi, Pieter C. Beerepoot, Paula C. Ortet, Ivan T. Jewett, Josue Alfaro-Lopez, Sorabh Agarwal, Daniel La, Aaron Fulgham, John H. McGee, Keith Orford, Jonathan B. Hurov, Martin R. Tremblay, Gregory L. Verdine. Discovery of a HeliconTM peptide inhibitor of the beta-catenin-TCF interaction with in vivo activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3094.