Design of spiro-heterocyclic substituted diaminonaphthalene Keap1-Nrf2 protein-protein interaction inhibitors as novel anti-depressant agents

  • Eur J Med Chem. 2025 Oct 15:296:117848. doi: 10.1016/j.ejmech.2025.117848.
Yitong Chen  1 ,  Qingqing Qin  2 ,  Wenxin Ding  3 ,  Ruizhi Yu  3 ,  Rui Wang  3 ,  Hualong Ji  4 ,  Jianyu Yan  3 ,  Hao Ma  5 ,  Cheng-Shi Jiang  6 ,  Yi Sun  7 ,  Chunlin Zhuang  8
Affiliations
  • 1. School of Biological Science and Technology, University of Jinan, Jinan 250022, China; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
  • 2. The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China; School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
  • 3. The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
  • 4. School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
  • 5. School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China.
  • 6. School of Biological Science and Technology, University of Jinan, Jinan 250022, China. Electronic address: [email protected].
  • 7. Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, 639 Longmian Dadao, Jiangning District, Nanjing, 210009, China. Electronic address: [email protected].
  • 8. School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China; The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China. Electronic address: [email protected].
PMID: 40513368 DOI: 10.1016/j.ejmech.2025.117848
Abstract

Oxidative stress, inflammation and the Keap1-Nrf2 pathway are validated to be related to depression. Theoretically, modulating Keap1 and Nrf2 protein-protein interaction (PPI) should be an effective method to activate Nrf2 for the treatment of major depressive disorders. We previously reported NXPZ-2, a 1,4-diaminonaphthalene, as a Keap1-Nrf2 PPI inhibitor that exhibited promising effects in an Alzheimer's disease (AD) mouse model. However, its pharmacokinetic properties were limited. Herein, we, for the first time, developed a series of heterocyclic substituted diaminonaphthalenes by an "Escape from Flatland" strategy to improve sp3 hybridized carbons. These compounds exhibited strong binding affinity for Keap1. A crystallographic analysis revealed the high-resolution (1.44 Å) binding of CD-10 with the Keap1 protein, elucidating the complexity of CD-10's binding mechanism. In an LPS-stimulated BV2 cell model, CD-10 demonstrated the best anti-oxidative stress and anti-inflammatory potential. Furthermore, CD-10's ability to penetrate the blood-brain barrier has been significantly improved. In a chronic unpredictable mild stress (CUMS) mouse model, treatment with CD-10 effectively alleviated anxiety and depressive behaviors and restored serum neurotransmitter levels by promoting Nrf2 nuclear translocation. Overall, our findings validate that the Keap1-Nrf2 PPI inhibitor holds promise as a preclinical candidate for the treatment of depression.

Keywords
Anti-depressant; Inhibitor; Keap1; Nrf2; Protein-protein interaction; Spiro-heterocyclic.
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