NDA Submission of Vepdegestrant (ARV-471) to U.S. FDA: The Beginning of a New Era of PROTAC Degraders

Abstract

RecommendationsT argeted protein degradation (TPD) technologies includ- ing proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) are emerging as paradigm-shifting therapeutic strategies for drug discovery.As depicted in Figure 1, the first peptide-based PROTAC was reported by Crews and co-workers in 2001. 1,2The development of PROTAC technology has progressed rapidly over the past two decades.This unique modality is revolutionizing the field of precision medicine, particularly in cancer treatment, completing the process from proof of concept (POC) validation to clinical transformation (Figure 1). [3][4]][5][6][7][8][9][10] Very recently, Arvinas and Pfizer have submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for vepdegestrant (ARV-471), an orally bioavailable PROTAC protein degrader targeting the estrogen receptor (ER), for patients with ESR1-mutated, ER+/HER2-advanced or metastatic breast cancers, according to a press release from Arvinas on June 6, 2025. 11This NDA application is based on positive results from the Phase 3 VERITAC-2 trial, indicating that vepdegestrant is anticipated to be the first FDA-approved PROTAC degrader.Such an exciting milestone marks the beginning of a new era of PROTAC degraders, tremendously inspiring PROTAC technology development and its growing impact on drug discovery and clinical trials.As alternatives to traditional small molecule inhibitors, PROTACs are a novel class of molecules that work by selectively degrading disease-causing their function. [12][13]][14][15][16][17][18] PROTACs represent a truly transformative approach to drug discovery and belong to the family of small molecule chemical inducers of proximity (CIPs). 19,20These heterobifunctional molecules consist of three components, including a binder for the protein-of-interest (POI), a binder for the E3 ligase, and a connecting linker.PROTACs induce the formation of a ternary complex of POI-PROTAC-E3, resulting in polyubiquitination and proteasomal degradation of the POI by hijacking inherent ubiquitin-proteasome system (UPS) in the human body (Figure 2A).PROTACs offer several attractive advantages compared to small molecule inhibitors. 2,7,8,12,16,17The most unique feature of PROTACs is that they induce POI degradation at a substoichiometric amount, acting as chemical catalysts.PROTACs take an "event-driven" mode instead of the "occupancy-driven" mode by small molecules inhibitors.PROTACs can thus mitigate the off-target effects of small molecular inhibitors with high systematic exposure to make sure sufficient effect.PROTACs take effect by eliminating the POI rather than mere inhibition like inhibitors.Thus, ligands with relatively low binding affinity for the POIs are also feasible for developing PROTACs.PROTACs demonstrate the potential to overcome drug resistance caused by mutations in the binding pocket of the POIs.PROTACs abrogate not only the catalytic function of the POIs but also the scaffold function, exhibiting higher efficacy than inhibitors.PROTACs can also induce the degradation of traditionally considered "undruggable" targets without active binding pockets or potent ligands, largely expanding the scope of target proteins.However, PROTACs often have relatively large molecular weight compared to small molecule inhibitors and violate Lipinski's rule of five (Ro5), which may cause limited druglike properties, including poor aqueous solubility, cell permeability, and metabolic stability.Such concerns have been allayed by recent positive clinical results with oral PROTACs released by biopharmaceutical companies like Arvina, Kymera Therapeutics, and Nurix Therapeutics. 11,[21][22]][23][24] To date, an online database reveals that 6,111 PROTACs targeting the degradation of over 200 POIs have been synthesized and investigated. [25][26]6][27] More than 30 PROTAC degraders have entered clinical trials, conferring therapeutic benefits (Table 1). 28 The most advanced PROTAC is vepdegestrant (ARV-471, PF-07850327, Figure 2B), with the NDA submission to FDA as aforementioned. 29Inspired by the great success of PROTACs, 13 several new CIPs beyond degradation have also been developed, 20,30 including regulated induced proximity targeting chimeras (RIPTACs), [31][32][33] deubiquitinase-targeting chimeras (DUBTACs), 34-37 enhancement-targeting chimeras (ENTACs), 38 RESTORACs, 39 phosphorylation-inducing chimeras (PHICs), 40 phosphatase-recruiting chimeras (PhoRCs), 41,42 phosphorylation-targeting chimeras (PhosTACs), 43 dephosphorylation-targeting chimeras (DEPTACs), 44 acetylation tagging system (AceTAG), 45,46 and transcriptional/epigenetic CIPs (TCIPs). [47][48]][49] Vepdegestrant is a potent, selective, orally bioavailable small molecule ER PROTAC degrader (Figure 2B). 50Vepdegestrant as a heterobifunctional molecule consists of lasofoxifene-based ER binding moiety, lenalidomide-based E3 ligase CRBN binding moiety, and a rigid N-containing heterocycle linker.

Topics & Concepts