A structure-activity relationship study of Forkhead Domain Inhibitors (FDI): The importance of halogen binding interactions

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.