Discovery of novel rigid STING PROTAC degraders as potential therapeutics for acute kidney injury

Abstract

Acute kidney injury (AKI) is a critical condition resulting from intrinsic immune overactivation for which no ideal therapeutic agent is available. The development of therapeutic drugs with new targets and mechanism has become one of the important challenges in the pharmaceutical field. The interferon gene stimulating protein (STING) directly regulates the intrinsic immune processes and is a potential target for AKI therapy. Herein, we designed synthesized and evaluated a series of novel STING-PROTAC degraders via a rigid strategy. Among them, compound ST9 performed the highest degradation capacity with a DC₅₀ of 0.62 μM in THP-1 cells. In a cisplatin-induced HK-2 cell model, ST9 could down-regulate the STING/NF-κB signaling axis and thus inhibit the expression of inflammatory factors. Additionally, ST9 showed a significantly improved metabolic stability profile. Furthermore, ST9 displayed favorable in vivo anti-AKI efficacy and has no toxic side effects on other organs. These results suggest that the novel rigid STING-PROTAC ST9 has clinical potential as a renoprotective agent for the treatment/prevention of acute kidney injury.