Past and future of the mitotic spindle as an oncology target

Wood, Kenneth W.; Cornwell, William D.; Jackson, Jeffrey R.

doi:10.1016/s1471-4892(01)00064-9

Cited by 249 publications

(157 citation statements)

References 48 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…Recently, the clinical use of some tubulin inhibitors, such as taxanes and vinca alkaloids, has been limited by neurotoxicity and drug resistance [5,6] . Therefore, new small-molecule tubulin-binding inhibitors must be developed with novel modes of action [5,7,8] . The development of this type of drug is focused on the design of novel tubulin inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking

et al. 2014

View full text Add to dashboard Cite

Aim:To construct a quantitative pharmacophore model of tubulin inhibitors and to discovery new leads with potent antitumor activities. Methods: Ligand-based pharmacophore modeling was used to identify the chemical features responsible for inhibiting tubulin polymerization. A set of 26 training compounds was used to generate hypothetical pharmacophores using the HypoGen algorithm. The structures were further validated using the test set, Fischer randomization method, leave-one-out method and a decoy set, and the best model was chosen to screen the Specs database. Hit compounds were subjected to molecular docking study using a Molecular Operating Environment (MOE) software and to biological evaluation in vitro. Results: Hypo1 was demonstrated to be the best pharmacophore model that exhibited the highest correlation coefficient (0.9582), largest cost difference (70.905) and lowest RMSD value (0.6977). Hypo1 consisted of one hydrogen-bond acceptor, a hydrogen-bond donor, a hydrophobic feature, a ring aromatic feature and three excluded volumes. Hypo1 was validated with four different methods and had a goodness-of-hit score of 0.81. When Hypo1 was used in virtual screening of the Specs database, 952 drug-like compounds were revealed. After docking into the colchicine-binding site of tubulin, 5 drug-like compounds with the required interaction with the critical amino acid residues and the binding free energies <-4 kcal/mol were selected as representative leads. Compounds 1 and 3 exhibited inhibitory activity against MCF-7 human breast cancer cells in vitro. Conclusion: Hypo1 is a quantitative pharmacophore model for tubulin inhibitors, which not only provides a better understanding of their interaction with tubulin, but also assists in discovering new potential leads with antitumor activities.

show abstract

Section: Introductionmentioning

confidence: 99%

Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Drugs that perturb mitosis have proven clinically effective in the treatment of many cancers (1). Despite the diverse array of essential spindle proteins that could be exploited as targets for the discovery of novel cancer therapies, all spindle-targeted therapeutics in clinical use today act on only one protein, tubulin.…”

Section: Introductionmentioning

confidence: 99%

“…Regions outside the motor domains of kinesin family members are quite divergent and play important roles in translating force generated by the motor domain to specific intracellular cargos (3). Several kinesins play essential roles in mitotic spindle assembly and function (1).…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of a Kinesin Inhibitor

et al. 2004

View full text Add to dashboard Cite

Several members of the kinesin family of microtubule motor proteins play essential roles in mitotic spindle function and are potential targets for the discovery of novel antimitotic cancer therapies. KSP, also known as HsEg5, is a kinesin that plays an essential role in formation of a bipolar mitotic spindle and is required for cell cycle progression through mitosis. We identified a potent inhibitor of KSP, CK0106023, which causes mitotic arrest and growth inhibition in several human tumor cell lines. Here we show that CK0106023 is an allosteric inhibitor of KSP motor domain ATPase with a K i of 12 nM. Among five kinesins tested, CK0106023 was specific for KSP. In tumor-bearing mice, CK0106023 exhibited antitumor activity comparable to or exceeding that of paclitaxel and caused the formation of monopolar mitotic figures identical to those produced in cultured cells. KSP was most abundant in proliferating human tissues and was absent from cultured postmitotic neurons. These findings are the first to demonstrate the feasibility of targeting mitotic kinesins for the treatment of cancer.

show abstract

“…Dans les cellules somatiques, les centrosomes ont une activité de nucléation des microtubules dominante par rapport à celle des chromosomes, et dictent la bipolarité du fuseau mitotique. Les vinca-alcaloïdes, incluant la vinblastine et la vincristine, sont les premières drogues antimitotiques identifiées provoquant une malformation du fuseau mitotique [34]. Elles ont pour cible la sous-unité β de la tubuline et dépolymérisent les microtubules.…”

Section: Dynéineunclassified

“…La vinblastine et la vincristine sont couramment utilisées dans le traitement de certains cancers (cancer des testicules, maladie de Hodgkin, leucémie lymphocytaire aiguë). Puis, la découverte des taxanes (paclitaxel et docé-taxel) et de leur impressionnante efficacité anti-tumorale a relancé l'intérêt des poisons de la tubuline [34,35]. Les taxanes se distinguent des autres drogues antimitotiques par un mécanisme d'action bien particulier: ils stimulent en effet la polymérisation de la tubuline et empêchent la dépolymérisation des microtubules.…”

Section: Dynéineunclassified