| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T28484 | ||||
| Target Name | Kinesin-like protein KIF11 | ||||
| Target Type | Clinical Trial |
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| Drug Potency against Target | Ispinesib | Drug Info | Ki = 0.6 nM | ||
| Action against Disease Model | Ispinesib | In preclinical studies, ispinesib inhibited growth in a wide range of h uMan and murine cell lines with IC50 values of 1.2-9.5?nM. Treatment of SKOV3 ovarian t uMour cells in vitro with 20?nM of ispinesib, or a Colo 205 colon cancer murine xenograft model with 30?mg?kg?1 of intraperitoneal ispinesib, caused mitotic arrest with cells demonstrating unseparated centrosomes and monopolar mitotic spindles. | [552795] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Eg5 is a plus end directed kinesin related motor protein (KRP) previously shown to be involved in the assembly and maintenance of the mitotic spindle. KRPs are molecular motors capable of generating forces upon microtubules (MTs) in dividing cells and driving structural rearrangements necessary in the developing spindle. In vitro experiments demonstrate that loss of Eg5 results in cell cycle arrest and defective centrosome separation resulting in the development of monopolar spindles. Here we describe mice with a genetrap insertion in Eg5. Heterozygous mutant mice appearphenotypically normal. In contrast, embryos homozygous for the Eg5 null allele recovered at embryonic days 2.5-3.5 display signs of a proliferation defect as reduced cell n uMbers and failure of compaction and progression to the blastocyst stage was observed. These data, in conjunction with previous in vitro data, suggest that loss of Eg5 results in abnormal spindle structure, cell cycle arrest and thereby reduced cell proliferation of early cleavage pre-implantation embryos. These observations further support the conclusion that Eg5 is essential for cell division early in mouse development, and that maternal contribution may sustain the embryo through the maternal to zygotic transition at which point supplies of functional Eg5 are exhausted, preventing further cell cleavage | ||||
| References | |||||
| Ref 552795 | A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours. Br J Cancer. 2008 Mar 11;98(5):894-9. doi: 10.1038/sj.bjc.6604264. Epub 2008 Mar 4. | ||||
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