S-Trityl-L-cysteine Is a Reversible, Tight Binding Inhibitor of the Human Kinesin Eg5 That Specifically Blocks
نویسندگان
چکیده
From the Laboratoire des Protéines du Cytosquelette and Laboratoire de Moteurs Moléculaires, Institut de Biologie Structurale (Commissariat à l’Energie Atomique-CNRS-UJF), 41 Rue Jules Horowitz, 38027 Grenoble Cedex 01, France, Laboratoire du Cytosquelette, INSERM Unite 366, Commissariat à l’Energie Atomique, 38054 Grenoble Cedex 9, France, Laboratoire de Chimie Organique Appliquée, Institut Gilbert-Laustriat, CNRS, Université Louis Pasteur, Faculté de Pharmacie, 74 Route du Rhin, 67401 Illkirch Cedex, France, **Marie Curie Research Institute, Oxted RH8 0TL, United Kingdom, and the Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213
منابع مشابه
S-trityl-L-cysteine is a reversible, tight binding inhibitor of the human kinesin Eg5 that specifically blocks mitotic progression.
Human Eg5, responsible for the formation of the bipolar mitotic spindle, has been identified recently as one of the targets of S-trityl-L-cysteine, a potent tumor growth inhibitor in the NCI 60 tumor cell line screen. Here we show that in cell-based assays S-trityl-L-cysteine does not prevent cell cycle progression at the S or G(2) phases but inhibits both separation of the duplicated centrosom...
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Human Eg5, a member of the kinesin superfamily, plays a key role in mitosis, as it is required for the formation of a bipolar spindle. We describe here the first in vitro microtubule-activated ATPase-based assay for the identification of small-molecule inhibitors of Eg5. We screened preselected libraries obtained from the National Cancer Institute and identified S-trityl-L-cysteine as the most ...
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Human kinesin Eg5 plays an essential role in mitosis by separating duplicated centrosomes and establishing the bipolar spindle. Eg5 is an interesting drug target for the development of cancer chemotherapy, with seven inhibitors already in clinical trials. In the present paper, we report the crystal structure of the Eg5 motor domain complexed with a potent antimitotic inhibitor STLC (S-trityl-L-...
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The human mitotic kinesin Eg5 represents a novel mitotic spindle target for cancer chemotherapy. We previously identified S-trityl-l-cysteine (STLC) and related analogues as selective potent inhibitors of Eg5. We herein report on the development of a series of 4,4,4-triphenylbutan-1-amine inhibitors derived from the STLC scaffold. This new generation systematically improves on potency: the most...
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An exciting new basic medical research study shows that inhibition of the activity of the kinesin spindle protein Eg5 effectively blocks cell division and induces cell death in prostate cancer cells. The potent anticancer drug S(methoxytrityl)-L-cysteine (S(MeO)TLC) specifically blocks activity of Eg5 in prostate cancer cells, arrests cell division, induces cell death during mitosis and inhibit...
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