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

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

  • Biochem Biophys Res Commun. 2019 Nov 12;519(3):505-511. doi: 10.1016/j.bbrc.2019.09.028.
Masayoshi Yamane 1 Jun-Ichi Sawada 1 Naohisa Ogo 1 Mai Ohba 2 Takayuki Ando 2 Akira Asai 3
Affiliations

Affiliations

  • 1 Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
  • 2 Department of Pharmaceutical and Food Science, Shizuoka Institute of Environment and Hygiene, Shizuoka, Japan.
  • 3 Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan. Electronic address: aasai@u-shizuoka-ken.ac.jp.
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.

Keywords

CENP-E; Cell cycle; Kinesin; Mitosis; Small molecule inhibitors.

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