From Concept to Clinic: Vepdegestrant (ARV 471) Becomes the First Approved PROTAC Drug

Breast cancer (BC) is a major global public health problem. Classical therapies have limited success on the treatment of BC; therefore, new therapeutic options are needed. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that represent a revolutionary class of new drug candidates because they induce the degradation of harmful, undruggable proteins by activating the ubiquitination machinery of cells. Their unique mechanism of action offers several advantages over conventional drugs, but also disadvantages, as most of them are large molecules with unfavorable pharmacokinetic properties, which limits their bioavailability. Vepdegestrant (VeppanuTM) is an orally administered, estrogen receptor (ER) targeting chimera that was approved by the FDA on 1 May 2026, for the treatment of adults with ESR1-mutated advanced or metastatic breast cancer. Thus, vepdegestrant became the first-ever approved PROTAC drug. In this article, we briefly summarize the structure, mechanism of action, and key available pharmacokinetic and pharmacological data of vepdegestrant.