A New Recruitable E3 Ligase UHRF1 Supporting Targeted Protein Degradation: A Minimal Azide as a Recruitment Ligand

Abstract

ABSTRACT Targeted protein degradation represents a promising therapeutic strategy, yet its broader application is often limited by the scarcity of usable E3 ligases. Glutathione peroxidase 4 (GPX4) is a key target for inducing ferroptosis, but achieving sustained and potent inhibition remains challenging with conventional enzymatic inhibitors. Herein, we report the first small‐molecule GPX4 degraders that incorporate either electrophilic warheads or a minimal azide group as an E3 recruitment ligand. The azide‐based degrader DK‐5070 effectively drives potent GPX4 degradation, achieving a DC50 of 17.4 nM and a Dmax of 84%, thereby outperforming larger PROTAC‐based degraders. Notably, DK‑5070 exhibits potent antitumor activity both in vitro (IC50 = 47.21 nM) and in vivo (TGI = 41.8%), demonstrating significant efficacy as a GPX4 degrader. Mechanistic studies reveal that degradation is mediated through recruitment of the oncogenic E3 ligase UHRF1, which is frequently overexpressed in tumors, underscoring the potential for tumor‐specific protein degradation. This demonstrated small‐molecule degraders that recruit UHRF1 to facilitate targeted degradation of GPX4. In this system, the azide group functions as a minimal recruitment ligand, thereby expanding the E3 ligase toolbox and offering a promising strategy for targeted cancer therapy.