Acute Kidney Injury (AKI) refers to a disease of rapid deterioration of renal function characterized by acute inflammation caused by overactivation of innate immunity [1]. According to epidemiological statistics, 13.3 million people worldwide are diagnosed with AKI and 1.7 million patients die from it every year [2]. Moreover, 19–31 % of patients with a benign course will progress to chronic and eventually end-stage renal disease, which imposes a great burden on families and society.

The stimulator of interferon gene (STING) is an innate immune molecule that was discovered primarily as a mediator of type I interferon (IFN–I) immune signaling [3,4]. Over the past decade, STING has gained extensive attention from the scientific community and pharmaceutical companies due to important physiological roles its target site function and the potential targetability by therapeutics [[5], [6], [7], [8]]. Accumulating evidence suggests that the activation of the innate immune pathway cGAS-STING is closely associated with mitochondrial (mt) damage and the inflammatory response that is successively induced [9]. In cisplatin-induced AKI, renal tubular mitochondrial injury leads to mtDNA leakage into the cell membrane to form a complex with cGAS, which catalyzes the production of cGAMP from GTP and ATP, and then induces the activation of STING protein multimerization, triggering the downstream signaling cascade [[10], [11], [12]]. On the one hand, STING can activate TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) to phosphorylate, and the phosphorylated IRF3 further dimerizes into the nucleus to activate the transcription of type I interferon and inflammatory cytokine genes [13]. On the other hand, STING enhances the expression of pro-inflammatory cytokines by activating the typical IκB kinase (IKK)-dependent nuclear factor kappa-B (NF-κB) signaling pathway [14]. Therefore, the aberrant activation of STING is closely related to the development of AKI and is an important potential target for AKI therapy.

In recent years, research on targeted inhibition of STING has become increasingly intensive, giving rise to a succession of STING inhibitors of different backbone types. As illustrated in Fig. 1A, C-170, a potent and covalent STING inhibitor, efficiently inhibits both mouse STING (mSTING) and human STING (hSTING) which has been used for autoinflammatory disease research [15]. Since the discovery of H-151 as a covalent inhibitor of STING palmitoylation, it has been the most widely used STING inhibitor in this field [15]. Dai's group discovered a representative indolyl-urea derivative 42, which exhibited potent inhibitory activity, acceptable pharmacokinetic properties, and a favorable in vivo safety profile [16]. SN-011 competes with cyclic dinucleotide (CDN) for the binding pocket of the STING dimer, blocking CDN binding and STING activation. In a study by Wang, computer-simulated docking was used to identify small molecules that bind to the STING CDN pocket. An analog SN-011 inhibited STING-dependent signaling with IC50 values of ∼100 nM and ∼500 nM for mouse and human cells, respectively. In addition, the discovery of the nitro fatty acid NO2-cLA [17], the naturally active molecules 13, 18 and AstinC further enriched the study of STING inhibitors [[18], [19], [20]]. Although potent STING inhibitors have been reported, their therapeutic potential is limited by insufficient activity, toxic side effects, and poor druggability. Therefore, the development of new strategies to target STING is expected to overcome the limitations of current STING inhibitors.

The emergence of proteolysis targeting chimeras (PROTACs) has revolutionized the landscape of drug discovery, offering a transformative approach to targeted protein degradation. PROTACs consist of a protein of interest (POI) binder, an E3 ligase recruiter, and a linker. PROTACs trigger the degradation of the POI by hijacking the ubiquitin-proteasome system (UPS) [21]. PROTACs possess unique advantages over traditional small molecule inhibitors, such as catalytic effect, long-lasting efficacy, improved selectivity, overcoming drug resistance, and degradation of undruggable targets [[22], [23], [24], [25]]. Therefore, the development of potent and selective STING-targeting PROTACs may offer a solution to potentially improve clinical outcomes in patients with STING dysregulation. Up to now, a number of STING PROTACs/PROTAC-like compounds have been identified (SP23, P8, SD02, UNC9036, Fig. 1B); however, their clinical translation is hampered by inadequate degradation potency and suboptimal pharmacokinetic (PK) properties [[26], [27], [28], [29]]. More importantly, current STING PROTACs mainly feature flexible linkers, the medicinal chemistry landscape of STING-PROTACs with rigid linkers remains largely unexplored, resulting in a substantial gap in our understanding of the structure-activity relationship (SAR).

In the present work, we designed and characterized a series of STING PROTAC molecules with rigid linkers, and examined the effects of linkage sites and trans double bonds. A selective and potent STING degrader, ST9, was identified through three rounds of structural optimization and conformational relationship analysis. We further demonstrated the potential efficacy of this drug candidate for the treatment of AKI.