Rational discovery of novel type-III FTF antagonists to competitively suppress TIF-2 coactivation in liver cancer

J Recept Signal Transduct Res. 2019 Aug;39(4):304-311. doi: 10.1080/10799893.2019.1690513. Epub 2019 Nov 22.

Abstract

The α-fetoprotein transcription factor (FTF) is a member of the nuclear receptor NR5A subfamily, which is involved in the pathogenesis of liver cancer and some other gastrointestinal cancers. The protein's transcriptional activity is regulated by binding TIF-2 coactivator at its coactivator-interacting site (CIS); suppression of the transcriptional activity has been recognized as a potential therapeutic strategy against cancer. Previously, small-molecule antagonists have been developed to target the ligand-binding site (LBS) of FTF ligand-binding domain, which simply occupy the site to exclusively block natural ligand entry (type-I antagonists) or destabilize the agonist conformation of activation helix 12 of the domain (type-II antagonists). Here, we describe the use of small-molecule competitors (type-III antagonists) to directly disrupt FTF-TIF-2 interaction by competitively targeting FTF CIS site. High-throughput virtual screening is performed against a structurally diverse, commercially available compound library to identify FTF CIS binders as competitor candidates, from which 12 hits are manually selected and their competitive potency with TIF-2 core binding sequence for FTF CIS site is tested with CC50 values up to 2.5 μM. Structural modeling analysis revealed that the competitive ligands can form a complicated network of noncovalent interactions to specifically or nonspecifically pack against FTF CIS site, thus preventing TIF-2 from binding to the site.

Keywords: coactivator; liver cancer; transcriptional mediator/intermediary factor 2; type-III antagonist; α-fetoprotein transcription factor.

MeSH terms

  • Drug Discovery*
  • High-Throughput Screening Assays
  • Humans
  • Ligands
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Molecular Docking Simulation
  • Molecular Structure
  • Nuclear Receptor Coactivator 2 / antagonists & inhibitors
  • Nuclear Receptor Coactivator 2 / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs / drug effects*
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Small Molecule Libraries / pharmacology*

Substances

  • Ligands
  • NCOA2 protein, human
  • NR5A2 protein, human
  • Nuclear Receptor Coactivator 2
  • Receptors, Cytoplasmic and Nuclear
  • Small Molecule Libraries