Mitotic Kinesin Inhibitors

Despite the diverse array of essential spindle proteins that could be exploited as targets for the discovery of novel cancer therapies, all spindle-targeted drugs in clinical use today that we have mentioned in this chapter act on only one protein, tubulin. Kinesins are motor proteins that function to transport organelles within cells, and one group of them (mitotic kinesins) move chromosomes along micro-tubules during cell division, playing essential roles in assembly and function of the mitotic spindle. Mitotic kinesins have an ATPase site that allows them to convert chemical energy into mechanical energy for the transport of DNA. They represent the first novel class of drug targets within mitosis to emerge in nearly 20 years.82

The most studied mitotic kinesin is the so-called kinesin spindle protein (KSP, Eg5), which functions at the earliest stages of mitosis to mediate centrosome separation and formation of a bipolar mitotic spindle. Eg5 interacts with micro-tubules in mitosis, but not with interphase microtubules, suggesting that its inhibitors may specifically target proliferating tumor tissue, thereby avoiding dose-limiting neuropathy observed with other antimicrotubule agents like taxanes or Vinca alkaloids. The first characterized small-molecule inhibitor of the motor protein Eg5 was monastrol, which is an allosteric inhibitor of the ATPase function of Eg5 that prevents ADP release by forming a ternary complex. The p-carboline derivative monastroline (HR22C16) was identified through a high-throughput microscopy-based forward-chemical-genetic screen.83 Another class of inhibitors of Eg5 function are quinazoline derivatives, which function via an allosteric mechanism similar to that of monastrol. Among them, ispinesib (SB-715992) has reached clinical trials in patients with a variety of refractory solid tumors.84




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