Accurate completion of cell division requires the timely formation of a fully functional mitotic spindle. Success or failure in this endeavor is at least partly dependent on tubulin polymerization dynamics and the activities of multiple accessory proteins whose role is to associate with and manipulate the tubulin polymer [1,2]. Among these accessory proteins are kinesins [3], motor proteins that bind to microtubules and utilize the energy derived from ATP hydrolysis to drive many of the structural changes required for spindle formation and function. The therapeutic potential of mitosis-specific members of this protein family, known as mitotic kinesins [4], was first demonstrated in 1999 with the finding that inhibition of kinesin spindle protein (KSP, Hs Eg5) with a small molecule produces cell cycle arrest in prometaphase and eventual cell death [5]. Soon thereafter, CK0106023 (1) was reported to shrink tumors in a xenograft model via an anti-mitotic mechanism of action [6]. Since then, agents targeting KSP have entered clinical trials. The following pages describe some of the recent progress made in the discovery and development of mitotic kinesin-targeted therapeutics and ongoing studies that may define the future potential of this target class.

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