The PROTAC milestone: FDA approval of vepdegestrant (ARV-471) for ESR1-mutated breast cancer.

Authors

Xin Lin, Hua Xiang, Guoshun Luo

Published in

Drug discovery today. Pages 104772. Aug 15, 2026. Epub Aug 15, 2026.

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.

PMID:
42603649
Bibliographic data and abstract were imported from PubMed on 16 Aug 2026.

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