2. Academic Validation
  3. Discovery of novel nitrofuran PROTAC-like compounds as dual inhibitors and degraders targeting STING

Discovery of novel nitrofuran PROTAC-like compounds as dual inhibitors and degraders targeting STING

  • Eur J Med Chem. 2024 Dec 5:279:116883. doi: 10.1016/j.ejmech.2024.116883.
Liang Xue 1,  Ruixue Liu 1,  Lican Zhang 1,  Tingting Qiu 1,  Lu Liu 2,  Ruijuan Yin 3,  Tao Jiang 4
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China.
  • 2 Marine Biomedical Research Institute of Qingdao, Qingdao, 266237, China.
  • 3 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China; Marine Biomedical Research Institute of Qingdao, Qingdao, 266237, China. Electronic address: yinruijuan@ouc.edu.cn.
  • 4 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Qingdao Marine Science and Technology Center, Qingdao, 266237, China; Center for Innovative Drug Discovery, Greater Bay Area Institute of Precision Medicine (Guangzhou), Guangzhou, 511455, China. Electronic address: jiangtao@ouc.edu.cn.
PMID: 39303513 DOI: 10.1016/j.ejmech.2024.116883
Abstract

Aberrant activation of the innate immune molecule STING can initiate inflammation and autoimmune diseases. Small molecule inhibitors targeting STING have demonstrated therapeutic efficacy against these conditions. Moreover, employing degradants to target STING represents a novel approach to drug design strategy. Consequently, we have designed and synthesized a series of covalent degradants targeting STING. Among them, compound P8 exhibited the highest degradation capacity, with a 24-h DC50 of 2.58 μM in THP-1 cells. In THP-1 cells, P8 specifically degraded STING proteins through the lysosomal pathway, acting as dual a degrader and inhibitor to manifest anti-inflammatory effects. Conversely, in RAW264.7 cells, P8 solely acted as an inhibitor without exhibiting degradative capacity towards the STING protein level. Additionally, P8 displayed renal-protective properties in a cisplatin-induced acute kidney injury model. These results highlight the significant potential of further investigating compound P8.

Keywords

Autoimmune diseases; Inflammatory; Lysosomal pathway; STING degraders.

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