2. Academic Validation
  3. Development of STING degrader with double covalent ligands

Development of STING degrader with double covalent ligands

  • Bioorg Med Chem Lett. 2024 Feb 24:102:129677. doi: 10.1016/j.bmcl.2024.129677.
Miki Nakamura 1,  Nobumichi Ohoka 2,  Norihito Shibata 3,  Takao Inoue 4,  Genichiro Tsuji 5,  Yosuke Demizu 6
Affiliations

Affiliations

  • 1 Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Division of Pharmaceutical Science of Okayama University, 1-1-1, Tsushimanaka, Kita 700-8530, Japan; Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
  • 2 Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan. Electronic address: [email protected].
  • 3 Division of Biochemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
  • 4 Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
  • 5 Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan. Electronic address: [email protected].
  • 6 Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Division of Pharmaceutical Science of Okayama University, 1-1-1, Tsushimanaka, Kita 700-8530, Japan; Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Yokohama, Kanagawa 230-0045, Japan. Electronic address: [email protected].
PMID: 38408510 DOI: 10.1016/j.bmcl.2024.129677
Abstract

Stimulator of interferon genes (STING), a homodimeric membrane receptor localized in the endoplasmic reticulum, plays a pivotal role in signaling innate immune responses. Inhibitors and proteolysis-targeting chimeras (PROTACs) targeting STING are promising compounds for addressing autoinflammatory and autoimmune disorders. In this study, we used a minimal covalent handle recently developed as the ligand portion of an E3 ligase. The engineered STING degrader with a low molecular weight compound covalently binds to STING and E3 ligase. Degrader 2 showed sustained STING degradation activity at lower concentrations (3 µM, 48 h, about 75 % degradation) compared to a reported STING PROTAC, SP23. This discovery holds significance for its potential in treating autoinflammatory and autoimmune diseases, offering promising avenues for developing more efficacious STING-targeted therapies.

Keywords

Covalent ligand; Drug design; Protein degradation; STING.

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