title: A Novel Time-Dependent CENP-E Inhibitor with Potent Antitumor Activity.
abstract: 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.
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ohashi
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Ohori
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Iwai
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Nambu
authors.affiliation: DMPK Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Miyamoto
authors.affiliation: Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: Oncology Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Okaniwa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors*; D020090:Chromosome Segregation; D064593:Heterografts; D008677:Metaphase; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis; D008941:Spindle Apparatus / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D002868:Chromosomal Proteins, Non-Histone; C068688:centromere protein E