| RRC ID |
58062
|
| 著者 |
Yamane M, Sawada JI, Ogo N, Ohba M, Ando T, Asai A.
|
| タイトル |
Identification of benzo[d]pyrrolo[2,1-b]thiazole derivatives as CENP-E inhibitors.
|
| ジャーナル |
Biochem Biophys Res Commun
|
| Abstract |
Kinesin centromere-associated protein E (CENP-E) has emerged as a potential target for the development of anticancer drugs due to its involvement in the mitotic progression of the cell cycle. Although several CENP-E inhibitors have been reported, more knowledge of chemical structures and inhibitory mechanisms is necessary for developing CENP-E inhibitors. Here, we describe the identification of new CENP-E inhibitors. Screening of a small-molecule chemical library identified benzo[d]pyrrolo[2,1-b]thiazole derivatives, including 1, as compounds with inhibitory activity against the microtubule-stimulated ATPase of the CENP-E motor domain. Among the mitotic kinesins examined, 1 selectively inhibited the kinesin ATPase activity of CENP-E. In a steady-state ATPase assay, 1 exhibited ATP-competitive behavior, which was different from the CENP-E inhibitor GSK923295. Compound 1 inhibited the proliferation of tumor-derived HeLa and HCT116 cells more efficiently than that of non-cancerous WI-38 cells. The inhibition of cell proliferation was attributed to the ability of 1 to induce apoptotic cell death. The compound showed antimitotic activity, which caused cell cycle arrest at mitosis via interference with proper chromosome alignment. We identified 1 and its derivatives as the lead compounds that target CENP-E, thus providing a new opportunity for the development of anticancer agents targeting kinesins.
|
| 巻・号 |
519(3)
|
| ページ |
505-511
|
| 公開日 |
2019-11-12
|
| DOI |
10.1016/j.bbrc.2019.09.028
|
| PII |
S0006-291X(19)31749-8
|
| PMID |
31530389
|
| MeSH |
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / chemistry
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Cell Cycle Checkpoints / drug effects
Cell Proliferation / drug effects
Chromosomal Proteins, Non-Histone / antagonists & inhibitors*
Chromosomal Proteins, Non-Histone / metabolism
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HCT116 Cells
HeLa Cells
Humans
Molecular Structure
Sarcosine / analogs & derivatives*
Sarcosine / chemistry
Sarcosine / pharmacology
Structure-Activity Relationship
Tumor Cells, Cultured
|
| IF |
2.985
|
| 引用数 |
0
|
| リソース情報 |
| ヒト・動物細胞 |
HeLa
WI-38 |
