The mitotic spindle is a microtubule-based machine that segregates a replicated set of chromosomes during cell division. Many cancer drugs alter or disrupt the microtubules that form the mitotic spindle. Microtubule-dependent molecular motors that function during mitosis are logical alternative mitotic targets for drug development. Eg5 (Kinesin-5) and Kif15 (Kinesin-12), in particular, are an attractive pair of motor proteins, as they work in concert to drive centrosome separation and promote spindle bipolarity. Furthermore, we hypothesize that the clinical failure of Eg5 inhibitors may be (in part) due to compensation by Kif15. In order to test this idea, we screened a small library of kinase inhibitors and identified GW108X, an oxindole that inhibits Kif15 in vitro. We show that GW108X has a distinct mechanism of action compared with a commercially available Kif15 inhibitor, Kif15-IN-1 and may serve as a lead with which to further develop Kif15 inhibitors as clinically relevant agents.

有丝分裂纺锤体是一种基于微管的机器，在细胞分裂过程中分离出一组复制的染色体。许多抗癌药物会改变或破坏形成有丝分裂纺锤体的微管。在有丝分裂期间起作用的依赖微管的分子马达是药物开发的合乎逻辑的替代有丝分裂靶标。Eg5（Kinesin-5）和Kif15（Kinesin-12）特别是一对有吸引力的运动蛋白，因为它们协同工作以驱动中心体分离并促进纺锤体双极性。此外，我们假设Eg5抑制剂的临床失败可能（部分）归因于Kif15的补偿。为了测试这个想法，我们筛选了一个小的激酶抑制剂文库，并鉴定了GW108X（一种在体外抑制Kif15的羟吲哚）。我们显示，与市售Kif15抑制剂Kif15-IN-1相比，GW108X具有独特的作用机理，并且可以作为进一步发展Kif15抑制剂作为临床相关药物的线索。