Ispinesib

Ispinesib is a cell-permeable, allosteric inhibitor of Eg5 (K_i app = 2.3 nM) with >10,000-fold selectivity for Eg5 over a range of other mitotic kinesins.^1,2 It induces a monopolar spindle phenotype, leading to the activation of a spindle assembly checkpoint, mitotic arrest, and subsequent cell death (GI₅₀s = 22-82 nM in colon, pancreas, prostrate, and lung cancer cells in vitro).³ At 10 mg/kg, ispinesib produces tumor regression of breast cancer cell xenografts in mice.⁴ It has also been used to halt the growth of treatment-resistant glioblastoma tumor-initiating cells, to prevent tumor initiation and self-renewal of a cancer stem cell population (EC₅₀ = 1.15 nM), and to reduce glioma cell invasion.⁵

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1. Good, J.A.D., Wang, F., Rath, O., et al. Optimized S-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models. J. Med. Chem. 56(5), 1878-1893 (2015).

2. Wang, F., Good, J.A.D., Rath, O., et al. Triphenylbutanamines: Kinesin spindle protein inhibitors with in vivo antitumor activity. J. Med. Chem. 55, 1511-1525 (2012).

3. Good, J.A.D., Skoufias, D.A., and Kozielski, F. Elucidating the functionality of kinesins: An overview of small molecule inhibitors. Semin. Cell Dev. Biol. 22(9), 935-945 (2011).

4. Purcell, J.W., Davis, J., Reddy, M., et al. Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer. Clin. Cancer Res. 16(2), 566-576 (2010).

5. Venere, M., Horbinski, C., Crish, J.F., et al. The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma. Sci. Transl. Med. 7(304), 1-12 (2015).