Synthetic Studies on Centromere-Associated Protein-E (CENP-E) Inhibitors: 2. Application of Electrostatic Potential Map (EPM) and Structure-Based Modeling to Imidazo[1,2-a]pyridine Derivatives as Anti-Tumor Agents

摘要

To develop centromere-associated protein-E (CENP-E) inhibitors for use as anticancer therapeutics, we designed novel imidazo[1,2-a]pyridines, utilizing previously discovered 5-bromo derivative la. By site-directed mutagenesis analysis, we confirmed the ligand binding site. A docking model revealed the structurally important molecular features for effective interaction with CENP-E and could explain the superiority of the inhibitor (S)-isomer in CENP-E inhibition vs the (R)-isomer based on the ligand conformation in the LS loop region. Additionally, electrostatic potential map (EPM) analysis was employed as a ligand-based approach to optimize functional groups on the imidazo[1,2-a]pyridine scaffold. These a]pyridine derivative (+)-(S)-12, which showed potent CENP-E (p-HH3) elevation (EC50: 180 nM), and growth inhibition demonstrated antitumor activity (T/C: 40%, at 75 mg/kg) in a efforts led to the identification of the 5-methoxy imidazo [1,2-inhibition (IC50: 3.6 nM), cellular phosphorylated histone H3 (GI(50): 130 nM) in HeLa cells. Furthermore, (+)-(S)-12 human colorectal cancer Colo205 xenograft model in mice.