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The PROTAC milestone: FDA approval of vepdegestrant (ARV-471) for ESR1-mutated breast cancer
Xin Lin1, Hua Xiang2, Guoshun Luo2
1State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, PR China.
Abstract:
The 2026 FDA approval of vepdegestrant (ARV-471), an oral proteolysis-targeting chimera (PROTAC) that targets the estrogen receptor α (ERα), represents a historic milestone for targeted protein degradation. Unlike selective estrogen receptor degraders that operate via occupancy-driven destabilization, vepdegestrant catalytically recruits the CRBN E3 ligase to ERα, inducing its ubiquitination and proteasomal degradation. In the Phase III VERITAC-2 trial, vepdegestrant significantly improved progression-free survival versus fulvestrant in ESR1-mutated, endocrine-resistant breast cancer. This milestone approval validates the PROTAC modality as a therapeutic platform, redefining oral beyond-Rule-of-5 design principles and opening new frontiers for induced-proximity medicines.
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