Inhibitors Of Kinesin Spindle Protein

KSP, also known as Hs Eg5, is a mitotic kinesin required in early mitosis for the formation of a bipolar mitotic spindle [7,8]. This protein exists as a homotetramer with an ability to bind to the oppositely polarized microtubules emanating from separate spindle poles. By coupling ATP hydrolysis with significant conformational mobility, KSP is able to move processively along microtubules via the coordinated action of paired motor domains arrayed at each end of the homotetramer. When bound to two microtubules, both ends of KSP attempt to move in the direction away from centrosomes, forcing spindle poles apart to create a bipolar mitotic spindle. Hence, inhibition of KSP causes mitotic arrest with the formation of monopolar mitotic spindles that result from failed centrosome separation. In addition, by acting on an accessory protein rather than on the microtubule cyto-skeleton itself, agents targeting KSP would be expected to avoid the peripheral neuropathies associated with anti-microtubule agents. Mitotic arrest with small molecule inhibitors has been shown to result in cell death on a number of tumor cell lines both in vitro and in vivo that, along with an expectation of reduced neural toxicity, serves as the basis for several ongoing anti-mitotic drug discovery programs [9,10].

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