Discovery of indolyl-urea compounds as effective STING PROTAC degraders for the treatment of acute kidney injury

  • Bioorg Chem. 2026 Jun 26:180:110165. doi: 10.1016/j.bioorg.2026.110165.
Peng Zhou  1 ,  Yaya Peng  1 ,  Tingting Zhang  1 ,  Gen Yang  1 ,  Xiangxiang Cao  2 ,  Jinliang Ma  3 ,  Wenpei Dong  4 ,  Changpo Chen  5
Affiliations
  • 1. Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China.
  • 2. Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China; College of Life Science and Technology, North Henan Medical University, Xinxiang, Henan 43003, PR China.
  • 3. Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China. Electronic address: [email protected].
  • 4. Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China. Electronic address: [email protected].
  • 5. Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, PR China. Electronic address: [email protected].
PMID: 42372458 DOI: 10.1016/j.bioorg.2026.110165
Abstract

The aberrant activation of stimulator of interferon genes (STING) signaling pathway is closely associated with the development of inflammatory and immune- associated diseases. Targeting and suppressing the STING signaling cascade represents a crucial strategy for treating related immune disorders by inhibitors or degraders. In this research, a series of PROTAC molecules targeting STING protein were designed and synthesized with the pharmacophore of C170, SN011, H151 as STING protein Binders linked to E3 Ligase ligands. Among these analogs, Compound Zp17 demonstrated favorable degradation potency in THP-1 cells with DC50 of 956 nM, and exhibited inhibition activity in RAW-Lucia cells with IC50 of 1.06 μM. Zp17 illustrated superior STING degradation activity and exhibited significantly lower cytotoxicity compared to SP23 in vitro. In mouse acute kidney injury (AKI) model, Zp17 effectively alleviated renal function impairment induced by cisplatin. Collectively, compound Zp17 warrants further investigation as PROTAC degrader of STING.

Keywords
Anti-inflammatory; H151 analogs; STING-PROTAC.
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