2. Academic Validation
  3. Phenotype-based screening rediscovered benzopyran-embedded microtubule inhibitors as anti-neuroinflammatory agents by modulating the tubulin-p65 interaction

Phenotype-based screening rediscovered benzopyran-embedded microtubule inhibitors as anti-neuroinflammatory agents by modulating the tubulin-p65 interaction

  • Exp Mol Med. 2022 Dec;54(12):2200-2209. doi: 10.1038/s12276-022-00903-z.
Junhyeong Yim 1,  Jaeseok Lee 2,  Sihyeong Yi 3,  Ja Young Koo 3,  Sangmi Oh 3,  Hankum Park 3 4,  Seong Soon Kim 5,  Myung Ae Bae 5 6,  Jongmin Park 7 8,  Seung Bum Park 9 10
Affiliations

Affiliations

  • 1 Department of Biophysics and Chemical Biology, Seoul National University, Seoul, 08826, Korea.
  • 2 Department of Chemistry, Kangwon National University, Chuncheon, 24341, Korea.
  • 3 CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul, 08826, Korea.
  • 4 Department of Dental Sciences, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 08826, Korea.
  • 5 Bio Platform Technology Research Center, Korea Research Institute of Chemical Technology, Daejeon, 34114, Korea.
  • 6 Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon, 34114, Korea.
  • 7 Department of Chemistry, Kangwon National University, Chuncheon, 24341, Korea. [email protected].
  • 8 Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon, 24341, Korea. [email protected].
  • 9 Department of Biophysics and Chemical Biology, Seoul National University, Seoul, 08826, Korea. [email protected].
  • 10 CRI Center for Chemical Proteomics, Department of Chemistry, Seoul National University, Seoul, 08826, Korea. [email protected].
PMID: 36509830 DOI: 10.1038/s12276-022-00903-z
Abstract

Neuroinflammation is one of the critical processes implicated in central nervous system (CNS) diseases. Therefore, alleviating neuroinflammation has been highlighted as a therapeutic strategy for treating CNS disorders. However, the complexity of neuroinflammatory processes and poor drug transport to the brain are considerable hurdles to the efficient control of neuroinflammation using small-molecule therapeutics. Thus, there is a significant demand for new chemical entities (NCEs) targeting neuroinflammation. Herein, we rediscovered benzopyran-embedded tubulin inhibitor 1 as an anti-neuroinflammatory agent via phenotype-based screening. A competitive photoaffinity labeling study revealed that compound 1 binds to tubulin at the colchicine-binding site. Structure-activity relationship analysis of 1's analogs identified SB26019 as a lead compound with enhanced anti-neuroinflammatory efficacy. Mechanistic studies revealed that upregulation of the tubulin monomer was critical for the anti-neuroinflammatory activity of SB26019. We serendipitously found that the tubulin monomer recruits p65, inhibiting its translocation from the cytosol to the nucleus and blocking NF-κB-mediated inflammatory pathways. Further in vivo validation using a neuroinflammation mouse model demonstrated that SB26019 suppressed microglial activation by downregulating lba-1 and proinflammatory cytokines. Intraperitoneal administration of SB26019 showed its therapeutic potential as an NCE for successful anti-neuroinflammatory regulation. Along with the recent growing demands on tubulin modulators for treating various inflammatory diseases, our results suggest that colchicine-binding site-specific modulation of tubulins can be a potential strategy for preventing neuroinflammation and treating CNS diseases.

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