GPX4-AUTAC is an autophagy-mediated degrader (AUTAC) targeting GPX4. It consists of the inhibitor ML162-yne, a degradation tag FBnG, and a glycol linker. GPX4-AUTAC facilitates the ubiquitination of GPX4 by the E3 ligase TRAF6 and enhances its interaction with GPX4 and p62, leading to selective autophagy-dependent degradation of GPX4. This compound significantly induces ferroptosis and demonstrates potent anticancer activity in breast cancer cells, patient-derived organoids (PDOs), and MDA-MB-231 tumor xenograft mouse models. It shows strong synergy when used in combination with Sulfasalazine (SAS) or chemotherapy drugs (Paclitaxel or Cisplatin).
