Synthetic studies of centromere-associated protein-E (CENP-E) inhibitors: 1.Exploration of fused bicyclic core scaffolds using electrostatic potential map

Centromere-associated protein-E (CENP-E), a mitotic kinesin that plays an important role in mitotic progression, is an attractive target for cancer therapeutic drugs. For the purpose of developing novel CENP-E inhibitors as cancer therapeutics, we investigated a fused bicyclic compound identified by...

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Published in:Bioorganic & medicinal chemistry 2013-09, Vol.21 (17), p.5488-5502
Main Authors: Hirayama, Takaharu, Okaniwa, Masanori, Imada, Takashi, Ohashi, Akihiro, Ohori, Momoko, Iwai, Kenichi, Mori, Kouji, Kawamoto, Tomohiro, Yokota, Akihiro, Tanaka, Toshimasa, Ishikawa, Tomoyasu
Format: Article
Language:English
Subjects:
4-Oxo-4,5-dihydrothieno[3,4-c]pyridine-6-carboxamide
Amides - chemical synthesis
Amides - chemistry
Amides - metabolism
Binding Sites
Bridged Bicyclo Compounds - chemistry
CENP-E
chemistry
Chromosomal Proteins, Non-Histone - antagonists & inhibitors
Chromosomal Proteins, Non-Histone - metabolism
drugs
Electrostatic potential map (EPM)
enzyme inhibition
HeLa Cells
histones
Histones - metabolism
Humans
Imidazo[1,2-a]pyridine
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - metabolism
inhibitory concentration 50
kinesin
Molecular Docking Simulation
Protein Binding
Protein Structure, Tertiary
pyridines
Pyridines - chemical synthesis
Pyridines - chemistry
Pyridines - metabolism
screening
Static Electricity
Structure-Activity Relationship
therapeutics
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Summary:Centromere-associated protein-E (CENP-E), a mitotic kinesin that plays an important role in mitotic progression, is an attractive target for cancer therapeutic drugs. For the purpose of developing novel CENP-E inhibitors as cancer therapeutics, we investigated a fused bicyclic compound identified by high throughput screening, 4-oxo-4,5-dihydrothieno[3,4-c]pyridine-6-carboxamide 1a. Based on this scaffold, we designed inhibitors for efficient binding at the L5 site in CENP-E utilizing homology modeling as well as electrostatic potential map (EPM) analysis to enhance CENP-E inhibitory activity. This resulted in a new lead, 5-bromoimidazo[1,2-a]pyridine 7, which showed potent CENP-E enzyme inhibition (IC50: 50nM) and cellular activity with accumulation of phosphorylated histone H3 in HeLa cells. Our homology model and EPM analysis proved to be useful tools for the rational design of CENP-E inhibitors.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2013.05.067