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Updated: Jan 5, 2026

Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
Published on: December 21, 2019
A structure-activity relationship study of Forkhead Domain Inhibitors (FDI): The importance of halogen binding
Seyed Amirhossein Tabatabaei Dakhili1, David J Pérez1, Keshav Gopal1
1Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada.
Abstract:
The Forkhead boX M1 (FOXM1) protein is an essential transcription factor required for the normal activation of human cell cycle. However, increasing evidence supports a correlation between FOXM1 overexpression and the onset of several types of cancer. Based on a previously reported molecular modeling and molecular dynamics simulations (MD) study, we hypothesized the role of an essential halogen-bonding interaction between the 4-fluorophenyl group in the forkhead domain inhibitor-6 (FDI-6) and an Arg297 residue inside the FOXM1-DNA binding domain (DBD). To prove the importance of this binding interaction, we synthesized and screened ten FDI-6 derivatives possessing different groups at the 4-fluorophenyl position of the lead molecule. Briefly, we found that derivatives possessing a 4-chlorophenyl, 4-bromophenyl, or a 4-iodophenyl group, were equipotent to the original 4-fluorophenyl moiety present in FDI-6, whereas derivatives without this 4-halogen moiety were inactive. We also observed that positional isomers in which the halogen was relocated to positions 2- or 3- on the phenyl group were significantly less active. These results provide evidence to support the essential role of a 4-halophenyl bonding interaction, with the Arg297 residue in the FOXM1-DBD, to exert inhibition of transcriptional activity.
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