ArticleRedox biology2023
Development of KEAP1-targeting PROTAC and its antioxidant properties: In vitro and in vivo.
Article in Redox biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 30 citations in OpenAlex.
- The role of metals in cancer and the use of metal chelators as a potential treatment strategy.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2026Review
- Targeted degradation of hepatic KEAP1 mitigates drug-induced liver injury via dual boosting NRF2 and PGAM5 signaling.Redox biology · 2026Article
- Mapping Scientific Landscapes and Therapeutic Innovations of Targeted Protein Degradation: A Scientometric Review.Pharmaceutics · 2026Review
- Potential oncogenic risks of Keap1-targeting PROTACs: Caution warranted in drug design.Acta pharmaceutica Sinica. B · 2026Article
- Review
- Induced proximity-based therapeutic modalities.Nature reviews. Drug discovery · 2026Review
- EGFR inhibitor-resistant lung cancers exhibit collateral sensitivity to a covalent, cysteine-independent KEAP1 oligomerizing molecular bridge.Nature communications · 2026Article
- Identification and Functional Characterization of COPD Molecular Subtypes Based on Oxeiptosis-Related Genes via WGCNA and Machine Learning.International journal of chronic obstructive pulmonary disease · 2026Article
- Caffeic acid alleviates myocardial ischemia-reperfusion injury by directly targeting Keap1Journal of pharmaceutical analysis · 2025Article
- Chemical knockdown of Keap1 and homoPROTAC-ing allergic rhinitis.Acta pharmaceutica Sinica. B · 2025Article
- Synthesis, biological evaluation and clinical trials of Cereblon-based PROTACs.Communications chemistry · 2025Review
- Compound K-enriched Korean red ginseng prevents lung cancer progression by targeting cancer cells and fibroblasts.Journal of ginseng research · 2025Article
- CIP2A promotes inflammation and exacerbates osteoarthritis by targeting CEMIP.Cellular & molecular biology letters · 2025Article
- Thirty years of NRF2: advances and therapeutic challenges.Nature reviews. Drug discovery · 2025Review
- PTGES3 proteolysis using the liposomal peptide-PROTAC approach.Biology direct · 2024Article
- Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions.Bioconjugate chemistry · 2024Review
- Inhibition of Proliferation and Induction of Apoptosis in Prostatic Carcinoma DU145 Cells by Polysaccharides from YunnanMolecules (Basel, Switzerland) · 2024Article
- Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol.iScience · 2023Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Oxidative stress due to abnormal accumulation of reactive oxygen species (ROS) is an initiator of a large number of human diseases, and thus, the elimination and prevention of excessive ROS are important aspects of preventing the development of such diseases. Nuclear factor erythroid 2-related factor 2 (NRF2) is an essential transcription factor that defends against oxidative stress, and its function is negatively controlled by Kelch-like ECH-associated protein 1 (KEAP1). Therefore, activating NRF2 by inhibiting KEAP1 is viewed as a strategy for combating oxidative stress-related diseases. Here, we generated a cereblon (CRBN)-based proteolysis-targeting chimera (PROTAC), which we named SD2267, that induces the proteasomal degradation of KEAP1 and leads to NRF2 activation. As was intended, SD2267 bound to KEAP1, recruited CRBN, and induced the degradation of KEAP1. Furthermore, the KEAP1 degradation efficacy of SD2267 was diminished by MG132 (a proteasomal degradation inhibitor) but not by chloroquine (an autophagy inhibitor), which suggested that KEAP1 degradation by SD2267 was proteasomal degradation-dependent and autophagy-independent. Following KEAP1 degradation, SD2267 induced the nuclear translocation of NRF2, which led to the expression of NRF2 target genes and attenuated ROS accumulation induced by acetaminophen (APAP) in hepatocytes. Based on in vivo pharmacokinetic study, SD2267 was injected intraperitoneally at 1 or 3 mg/kg in APAP-induced liver injury mouse model. We observed that SD2267 degraded hepatic KEAP1 and attenuated APAP-induced liver damage. Summarizing, we described the synthesis of a KEAP1-targeting PROTAC (SD2267) and its efficacy and mode of action in vitro and in vivo. The results obtained suggest that SD2267 could be used to treat hepatic diseases related to oxidative stress.
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