Identification of benzo[d]pyrrolo[2,1-b]thiazole derivatives as CENP-E inhibitors

• Published in: Biochemical and biophysical research communications 2019-11, Vol.519 (3), p.505-511
• Main Authors: Yamane, Masayoshi, Sawada, Jun-ichi, Ogo, Naohisa, Ohba, Mai, Ando, Takayuki, Asai, Akira
• Format: Article
• Language: English
• Subjects: Cell cycle; CENP-E; Kinesin; Mitosis; Small molecule inhibitors
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.09.028

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. [Display omitted] •New CENP-E inhibitors with benzo[d]pyrrolo[2,1-b]thiazole structure were discovered.•One of the inhibitors prevents the CENP-E motor domain from binding to ATP.•It preferentially inhibits proliferation of tumor cells but not non-cancerous cells.•It causes a defect in chromosome alignment, thereby inducing mitotic arrest.