In Silico Discovery and Characterization of a Novel Nuclear Transcription Factor-Y (NF-Y) Inhibitor with Antimitogenic Properties

  • J Med Chem. 2026 Apr 9;69(7):8115-8129. doi: 10.1021/acs.jmedchem.5c03508.
Reza Ebrahimighaei  1 ,  Jon Lees  1 ,  Robin A Corey  2 ,  Boyi Xiao  2 ,  Christopher Williams  3 ,  Himali Y Godage  3 ,  Vealmurugan Sekar  1 ,  Hunaid Vohra  4 ,  Deborah Shoemark  2 ,  Andrew Newby  1 ,  Mark Bond  1
Affiliations
  • 1. Translational Health Sciences Bristol Medical School, University of Bristol, Bristol BS2 8HW, U.K.
  • 2. School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences Building, University of Bristol, BristolBS8 1TD, U.K.
  • 3. School of Chemistry, Faculty of Science, University of Bristol, Cantock's Close, Bristol BS8 1TS, U.K.
  • 4. Bristol Heart Institute, University Hospitals Bristol, NHS Foundation Trust, Bristol BS1 3NU, U.K.
PMID: 41858057 DOI: 10.1021/acs.jmedchem.5c03508
Abstract

Nuclear Transcription Factor-Y (NF-Y) is a transcription factor that binds CCAAT motifs to regulate gene expression, controlling cell proliferation, metabolism, and differentiation. NF-Y dysregulation contributes to diverse pathologies, including Cancer, neurological disorders, Cardiovascular Disease, and tissue fibrosis. Using in silico molecular docking, we screened a library of eight million compounds to identify molecules targeting a pocket on the NF-YB/NF-YC dimer. We identified one compound, designated NFYi5, that was able to reduce the NF-Y activity. NFYi5 reduced mRNA levels of NF-Y target genes, while sparing housekeeping gene expression, and inhibiting cell proliferation. Mechanistic studies revealed that NFYi5 impaired NF-Y-DNA binding and accelerated NF-YA protein degradation, reducing its half-life from 16.5 ± 1.5 h to 8.5 ± 0.7 h. Together, these data establish NFYi5 as a small-molecule that can reduce NF-Y activity and is associated with antimitogenic properties. This proof-of-concept study demonstrates that NF-Y is pharmacologically tractable and highlights NFYi5 as a potential lead compound for therapeutic development in NF-Y-driven diseases.

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