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.
Highlights
Antimitotic drugs targeting microtubule dynamics, such as taxanes and vinca alkaloids, are widely used in the clinical treatment of cancer [1]
Its inhibitory activity was sustained even at high ATP concentrations following 1-h preincubation with the centromereassociated protein E (CENP-E) motor domain (Fig 1A, blue line). The results of this investigation indicated that Cmpd-A is a time-dependent inhibitor that has the potential to overcome high ATP concentrations in cellular settings when it occupies the allosteric site of CENP-E
Cmpd-A potently suppressed the proliferation of HeLa cells in a concentration-dependent manner (GI50 = 80 nM) [29], and this antiproliferative effect was closely correlated with the percentage of phosphohistone H3 (pHH3)-positive cells. These results indicate that, consistent with the molecular mechanisms of CENP-E, mitotic aberration appears to be involved in the antiproliferative mechanism of Cmpd-A and that pHH3 is a potential surrogate PD marker that can be used to monitor the cellular activity of Cmpd-A
Summary
Antimitotic drugs targeting microtubule dynamics, such as taxanes and vinca alkaloids, are widely used in the clinical treatment of cancer [1]. Peripheral neuropathy is a major adverse effect of these drugs, presumably because they directly inhibit the assembly of microtubule structures even in non-dividing neural cells [2]. To reduce the incidence of this debilitating side effect, the components of mitotic spindles that are non-structural but essential for mitosis have recently attracted attention as target molecules for next-generation anticancer drugs. Eg5 ( called kinesin spindle protein; KSP) and centromereassociated protein E (CENP-E), are emerging as promising target molecules for anticancer drugs [3]. CENP-E has been reported to transport the pole-proximal chromosomes toward the metaphase plate, and PLOS ONE | DOI:10.1371/journal.pone.0144675 December 9, 2015
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