Kinesin-5/Eg5/KSP

Kinesin-5 (Eg5, also known as KSP or KIF11) is a plus-end-directed motor protein that drives mitotic spindle bipolarization by sliding anti-parallel microtubules apart^[1][2]. This motor operates as a homotetramer and contributes force to maintain spindle integrity during mitosis, ensuring accurate chromosome segregation^[1][2][3]. Mechanistically, Eg5 couples ATP hydrolysis to conformational changes that generate microtubule-directed movement, with microtubule binding accelerating its ATPase cycle and force production^[3]. In disease models, Eg5 is overexpressed in various cancers, including breast cancer and leukemia, where it supports uncontrolled proliferation and is a validated anticancer target^[2][4][5]. Compared with other mitotic kinesins, such as kinesin-12 (Kif15), Eg5 is uniquely required for centrosome separation, though compensatory pathways can mitigate inhibition under selective pressure^[6][7][8]. Small-molecule inhibitors, including monastrol, K858, SB-743921, and BRD9876, selectively block Eg5 ATPase activity or microtubule binding, causing mitotic arrest, apoptosis, or reduced angiogenesis in cancer and endothelial models^{[1][9][10][11]}. Some allosteric inhibitors overcome resistance mechanisms by targeting unique binding sites, whereas ATP-competitive inhibitors provide alternative strategies to circumvent Eg5 mutation-mediated drug resistance^[12][13]. These inhibitors have also been applied in mechanistic studies of spindle dynamics, neuronal transport, and angiogenesis, demonstrating broad utility in experimental and translational research^[14][11].