A Novel Time-Dependent CENP-E Inhibitor with Potent Antitumor Activity.

• Main Authors: Akihiro Ohashi, Momoko Ohori, Kenichi Iwai, Tadahiro Nambu, Maki Miyamoto, Tomohiro Kawamoto, Masanori Okaniwa
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2015-01-01
• Series: PLoS ONE
• Online Access: http://europepmc.org/articles/PMC4674098?pdf=render

Centromere-associated protein E (CENP-E) regulates both chromosome congression and the spindle assembly checkpoint (SAC) during mitosis. The loss of CENP-E function causes chromosome misalignment, leading to SAC activation and apoptosis during prolonged mitotic arrest. Here, we describe the biological and antiproliferative activities of a novel small-molecule inhibitor of CENP-E, Compound-A (Cmpd-A). Cmpd-A inhibits the ATPase activity of the CENP-E motor domain, acting as a time-dependent inhibitor with an ATP-competitive-like behavior. Cmpd-A causes chromosome misalignment on the metaphase plate, leading to prolonged mitotic arrest. Treatment with Cmpd-A induces antiproliferation in multiple cancer cell lines. Furthermore, Cmpd-A exhibits antitumor activity in a nude mouse xenograft model, and this antitumor activity is accompanied by the elevation of phosphohistone H3 levels in tumors. These findings demonstrate the potency of the CENP-E inhibitor Cmpd-A and its potential as an anticancer therapeutic agent.