Mitotic kinesin

In recent years there has been some interest in monastrol (62), a potentially important chemotherapeutic for cancer which acts as an inhibitor of mitotic kinesin Kappe and coworkers successfully synthesized racemic monastrol (62) using microwave-mediation in 60% yield from ethyl acetoacetate (6), 3-hydroxybenzaldehyde (63), and thiourea (3b) in the presence of PPE." ... 

Also nonkinase molecules might be important targets for anticancer drugs. For instance, the activity of the mitotic kinesin Eg5 (KSP, kinesin-5) can be inhibited by small molecules (e.g., monastrol, KSP-IA) resulting in mitotic defects associated with the induction of apoptosis. 

Benomyl was used in the mad and bub screens not because of its specific protein target but because of the perturbation of spindle assembly. In principle, the same experiments could have been done without knowing the protein target or by targeting a different component of the spindle. The generality of the spindle checkpoint has been demonstrated through the use of monastrol, a small-molecule inhibitor of the mitotic kinesin Eg5, which was identified in a screen for small molecules that arrest cells in mitosis without targeting tubulin (24). Monastrol treatment arrests cells in mitosis with monopolar spindles because Eg5 is required to separate the spindle poles. The inhibition of... 

Kapoor TM, Mayer TU, Coughlin ML, Mitchison TJ. Probing spindle assembly mechanisms with monastrol, a small molecule inhibitor of the mitotic kinesin, Eg5. J. CeU. Biol. 2000 150 975-988. 

Eg5 (Motor Protein and Mitotic Kinesin) -Accessible Active Site, More Amenable Cryptic Binding Site... 

Maliga, Z., Kapoor, T.M., and Mitchison, T.J. (2002) Evidence that monastrol is an allosteric inhibitor of the mitotic kinesin Eg5. Chem. Biol. 9, 989-96. 

Brier, S., Lemaire, D., DeBonis, S., Forest, E., and Kozielski, F. (2006) Molecular dissection of the inhibitor binding pocket of mitotic kinesin Eg5 reveals mutants that confer resistance to antimitotic agents. /. Mol. Biol. 360, 360-76. 

Rickert, K.W., Schaber, M., Torrent, M., et al. (2008) Discovery and biochemical characterization of selective ATP competitive inhibitors of the human mitotic kinesin KSP. Arch. Biochem. Biophys. 469, 220-31. 

The thio analogue of 511 with R2 = H and Ar = m-hydroxyphenyl named dimethylenastron was prepared as a racemic mixture by the reaction of m-hydroxy benzaldehyde with 1 and thiourea in the presence of polyphosphate ester under MW irradiation. It has a distinct cell permeable inhibition of the mitotic Kinesin, Eg5 which was more potent than monastrol (05MI1173). 

Kinesins can be divided into two broad functional groups— cytosolic and mitotic kinesins—on the basis of the nature of the cargo that they transport (Table 20-2). The functional differences between kinesins are related to their unique tall domains, which determine their cargoes. Cytosolic kinesins take part in vesicle and organelle transport they Include the classic axonal kinesin I, which has been shown to transport lysosomes and other organelles. Some cytosolic kinesins, however, transport one specific cargo. For example, KIFIB and its close relative KIFIA transport mitochondria and synaptic vesicles, respectively, to nerve terminals. Other cyrt osollc kinesins mediate the transport of secretory vesicles to the plasma membrane and the radial movement of ER... 

The dynamic instability of spindle microtubules at the other end, the (+) end, is critical to their capture of chromosomes during late prophase as the nuclear membrane begins to break down. By quickly lengthening and shortening at its (-k) end, a dynamic microtubule probes into the chromosome-rich environment of the cell. Sometimes the (+) end of a microtubule directly contacts a kinetochore, scoring a bull s-eye. More commonly, a kinetochore contacts the side of a microtubule and then slides along the microtubule to the (+) end in a process that includes cytosolic dynein and mitotic kinesins... 

Tao, W., South, V. J., Zhang, Y, Davide,J. P., Farrell, L., Kohl, N. E., et al. (2005). Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell, 8, 49-59. 

Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage, Cancer Cell 2005, 8,49-59. 

Monastrol Cultured cells Induces monopolar spindles Mitotic kinesin Eg5... 

R.H. Wade, F. Kozielski, In vitro screening for inhibitors of the human mitotic kinesin Eg5 with antimitotic and antitumor activities, Mol. Cancer Ther. 2004, 3, 1079-1090. 

Cross RA, McAinsh A (2014) Prime movers the mechanochemistry of mitotic kinesins. Nat Rev Mol Cell Bio 15 257... 

Huang R, Oh H, Arrendale A, Martin VA, Galan J, Workman EJ, Stout JR, Walczak CE, Tao WA, Borch RF et al (2013) Intracellular targets for a phosphotyrosine peptidomimetic include the mitotic kinesin, MCAK. Biochem Pharmacol 86 597-611... 

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