By Sir C V Raman
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Mol Cell 29:637–643 122. Stumpff J et al (2011) A tethering mechanism controls the processivity and kinetochoremicrotubule plus-end enrichment of the kinesin-8 Kif18A. Mol Cell 43:764–775 123. Antonio C et al (2000) Xkid, a chromokinesin required for chromosome alignment on the metaphase plate. Cell 102:425–435 124. Vernos I et al (1995) Xklp1, a chromosomal Xenopus kinesin-like protein essential for spindle organization and chromosome positioning. Cell 81:117–127 125. Brown KD, Wood KW, Cleveland DW (1996) The kinesin-like protein CENP-E is kinetochore-associated throughout poleward chromosome segregation during anaphase-A.
Evaluation of antitumour activity in mice with tumours developed from injected A2780 cells demonstrated MK-0731 inhibited tumour growth more effectively than paclitaxel administered on an optimised schedule. Significantly, MK-0731 also inhibited tumour growth in more rigorous tumour models developed from Pgp-overexpressing KB-V1 and paclitaxel resistant PTX10 cell lines. Based on its favourable efficacy, pharmacokinetic and safety profile, MK-0731 entered into clinical trials against solid tumours, where in agreement with preclinical models the dose limiting toxicity was neutropenia [25, 42].
1 Maximum tolerated dose National Cancer Institute No inhibition Overall response rate Pharmacokinetic P-glycoprotein Relapsed/refractory multiple myeloma Structure activity relationship S-trityl L-cysteine Introduction Interest in the mitotic kinesins as targets in cancer treatment began following the discovery of monastrol (Fig. 1), the first selective inhibitor of a mitotic kinesin . Monastrol was identified in a high throughput phenotypic screen designed to detect novel anti-mitotic agents, with exposure to HeLa cells producing a distinctive monoastral spindle phenotype, comparable to that observed by RNAi mediated Eg5 depletion [1, 2].