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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2015 Oct 22; Vol. 58 (20), pp. 8036-53. Date of Electronic Publication: 2015 Oct 01. - Publication Year :
- 2015
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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.
- Subjects :
- Animals
Binding Sites
Drug Design
HeLa Cells
Histones metabolism
Humans
Ligands
Mice
Mitosis drug effects
Models, Molecular
Mutagenesis, Site-Directed
Phosphorylation
Static Electricity
Structure-Activity Relationship
Xenograft Model Antitumor Assays
Antineoplastic Agents chemical synthesis
Antineoplastic Agents pharmacology
Chromosomal Proteins, Non-Histone antagonists & inhibitors
Pyridines chemical synthesis
Pyridines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 58
- Issue :
- 20
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26372373
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.5b00836