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^min/+ 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 G₁ 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^min/+ 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.

Adenomatous polyposis coli (APC) mutation; Colorectal cancer (CRC); Oncogenes; PROTAC; Ubiquitin–proteasome system (UPS); Wnt/β-catenin signaling.