C-Arg9-APCR3-VHL promotes β-catenin degradation via the VHL-mediated ubiquitin-proteasome system in APC-mutant colorectal cancer.

Mutations in the adenomatous polyposis coli (APC) gene are common in colorectal cancer (CRC) and result in deregulation of β-catenin, a key driver of tumor initiation and progression. Despite its central role, targeted degradation of β-catenin remains an unmet therapeutic need in APC-mutant CRC. This study introduces and evaluates C-Arg9-APCR3-VHL, a novel PROTAC designed to promote β-catenin degradation via the VHL-Mediated ubiquitin-proteasome pathway. The compound was synthesized as a cell-permeable PROTAC and tested for its pharmacological effects in APC-mutant CRC cell lines, xenograft tumor models, and APC mice. Key assessments included β-catenin expression and ubiquitination, cell cycle analysis, migration and invasion assays, tumor burden measurement, and systemic toxicity evaluation. C-Arg9-APCR3-VHL successfully induced β-catenin degradation through VHL-mediated ubiquitination and proteasomal clearance. In CRC cells, it reduced β-catenin levels, inhibited proliferation, induced G cell cycle arrest, and suppressed both migration and invasion. In vivo, the compound significantly inhibited tumor growth in xenografts and decreased adenoma burden in APC mice, all without signs of systemic toxicity. These findings highlight C-Arg9-APCR3-VHL as a promising and specific therapeutic candidate for the early intervention of APC-mutant colorectal cancer.