2. Academic Validation
  3. Bivalent inhibitors of the BTB E3 ligase KEAP1 enable instant NRF2 activation to suppress acute inflammatory response

Bivalent inhibitors of the BTB E3 ligase KEAP1 enable instant NRF2 activation to suppress acute inflammatory response

  • Cell Chem Biol. 2023 Dec 21:S2451-9456(23)00435-X. doi: 10.1016/j.chembiol.2023.12.005.
Mengchen Lu 1,  Jianai Ji 2,  Yifei Lv 2,  Jing Zhao 2,  Yuting Liu 2,  Qiong Jiao 2,  Tian Liu 2,  Yi Mou 3,  Qidong You 4,  Zhengyu Jiang 5
Affiliations

Affiliations

  • 1 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University Medical College, Suzhou 215123, China.
  • 2 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 3 College of Pharmacy and Chemistry and Chemical Engineering, Taizhou University, Taizhou 225300, China.
  • 4 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
  • 5 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
PMID: 38157852 DOI: 10.1016/j.chembiol.2023.12.005
Abstract

Most BTB-containing E3 Ligases homodimerize to recognize a single substrate by engaging multiple degrons, represented by E3 ligase KEAP1 dimer and its substrate NRF2. Inactivating KEAP1 to hinder ubiquitination-dependent NRF2 degradation activates NRF2. While various KEAP1 inhibitors have been reported, all reported inhibitors bind to KEAP1 in a monovalent fashion and activate NRF2 in a lagging manner. Herein, we report a unique bivalent KEAP1 inhibitor, biKEAP1 (3), that engages cellular KEAP1 dimer to directly release sequestered NRF2 protein, leading to an instant NRF2 activation. 3 promotes the nuclear translocation of NRF2, directly suppressing proinflammatory cytokine transcription. Data from in vivo experiments showed that 3, with unprecedented potency, reduced acute inflammatory burden in several acute inflammation models in a timely manner. Our findings demonstrate that the bivalent KEAP1 inhibitor can directly enable sequestered substrate NRF2 to suppress inflammatory transcription response and dampen various acute inflammation injuries.

Keywords

BTB E3 ligase; KEAP1; NRF2 activation; acute inflammation; bivalent inhibitor.

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