Abstract 6979: Development of orally bioavailable multi-targeted inhibitors of Wnt signaling for the treatment of colorectal cancer

Abstract Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States, projected to account for 7.6% of all new U.S. cancer cases in 2024. Hyperactivation of the Wnt/β-catenin signaling pathway is a key driver of CRC, with up to 96% of cases showing oncogenic Wnt activation. Increased Wnt activation contributes to tumor stemness, progression, and pathogenesis. Targeted therapies have been developed, but drug resistance can often occur, limiting effectiveness. In this work, a novel series of multi-targeted kinase inhibitors that target downstream members of the Wnt signaling pathway (DYRKs, CLKs, CDK7/8/19), along with PI3Kα, BRAF, and PDGFR have been developed. Our lead compound, DYR895, demonstrates improved Wnt signaling inhibition over phase 1b clinical candidate Cirtuvivint (WNT reporter EC50: 5.1 nM vs. 230 nM), while being well tolerated in mouse models (MTD >50 mg/kg) and orally bioavailable (F%: 81%). In an HCT-116 xenograft model, treatment with DYR895 resulted in reduced tumor growth and improved survival. Further optimization of DYR895 with the goal of reducing CNS exposure while enhancing Wnt inhibition led to the discovery of DYR1055, with a 10x improvement in affinity for some target kinases while maintaining key surrogate ADME attributes. Investigations into the efficacy of DYR1055 in disease models are ongoing. Citation Format: Sean Ginn, Samantha Rokey, Alessandra Fistrovich, Aidan McMahon, Timothy Chavez, Vasudha Tandon, Joaquina Nogales, Carly Cabel, Crystal Morales, Shravani Daptardar, Curtis Thorne, Sourav Banerjee, Christopher Hulme. Development of orally bioavailable multi-targeted inhibitors of Wnt signaling for the treatment of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6979.