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.
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| Abstract |
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 1a. 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 L5 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 efforts led to the identification of the 5-methoxy imidazo[1,2-a]pyridine derivative (+)-(S)-12, which showed potent CENP-E inhibition (IC50: 3.6 nM), cellular phosphorylated histone H3 (p-HH3) elevation (EC50: 180 nM), and growth inhibition (GI50: 130 nM) in HeLa cells. Furthermore, (+)-(S)-12 demonstrated antitumor activity (T/C: 40%, at 75 mg/kg) in a human colorectal cancer Colo205 xenograft model in mice.
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| Authors | Takaharu Hirayama, Masanori Okaniwa, Hiroshi Banno, Hiroyuki Kakei, Akihiro Ohashi, Kenichi Iwai, Momoko Ohori, Kouji Mori, Mika Gotou, Tomohiro Kawamoto, Akihiro Yokota, Tomoyasu Ishikawa |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 20 Pg. 8036-53 (Oct 22 2015) ISSN: 1520-4804 [Electronic] United States |
| PMID | 26372373 (Publication Type: Journal Article) |
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