Structure-based virtual screening towards the discovery of novel FOXM1 inhibitors

Future Med Chem. 2022 Feb;14(4):207-219. doi: 10.4155/fmc-2021-0282. Epub 2021 Nov 23.

Abstract

Aim: Given the importance of FOXM1 in the treatment of ovarian cancer, we aimed to identify an excellent specific inhibitor and examined its underlying therapeutic effect. Materials & methods: The binding statistics for FDI-6 with FOXM1 were calculated through computer-aided drug design. We selected XST-119 through virtual screening, performed surface plasmon resonance and in vitro cell antiproliferative activity analysis and evaluated its antitumor efficacy in a mouse model. Results: XST-119 had significantly higher affinity for FOXM1 and antiproliferative activity than FDI-6. XST-119 had a definite inhibitory activity in a xenograft mouse model. Conclusion: We identified XST-119, a FOXM1 inhibitor, with better efficacy for treatment of ovarian cancer. FOXM1 binding sites for small molecules are also highlighted, which may provide the foundation for further drug discovery.

Keywords: CADD; FOXM1; anticancer activity; ovarian cancer; structural similarity search.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • Forkhead Box Protein M1 / antagonists & inhibitors*
  • Forkhead Box Protein M1 / metabolism
  • Humans
  • Ligands
  • Mice
  • Molecular Docking Simulation
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / pathology
  • Structure-Activity Relationship
  • Thermodynamics

Substances

  • Antineoplastic Agents
  • Forkhead Box Protein M1
  • Ligands