A second generation KSP inhibitor, SB-743921, is a highly potent and active therapeutic in preclinical models of cancer

B11 Discovery and development of drugs that target mitosis continues to be an active and important area of cancer drug research. The primary goal for identifying new targeted antimitotic therapies is to inhibit targets that are highly specific to mitosis and result in more effective agents against tumor cells with less affects on non-dividing cells. The mitotic kinesin KSP (Eg5) is an essential mitotic enzyme with no role outside of mitosis. Several KSP inhibitors have been previously reported and multiple examples are being evaluated clinically. We sought to identify a second generation KSP inhibitor and characterize its activity in preclinical models of cancer. We discovered SB-743921, which is 5-fold more potent against the ATPase activity of KSP than ispinesib , the first KSP inhibitor to enter clinical trials. SB-743921 inhibits KSP (Eg5) with a Ki of 0.1 nM and has cytotoxic activity at less than 2 nM is a spectrum of tumor cell lines. We have demonstrated that SB-743921 is negative in a mouse model of peripheral neuropathy in which paclitaxel is positive. SB-743921 was shown to have activity against advanced human tumor xenografts Colo205 (complete regressions), MCF-7, SK-MES, H69, OVCAR-3 (complete and partial regressions), and HT-29, MX-1, MDA-MB-231, A2780 (tumor growth delay). Efficacy was dose-related, and in the most sensitive tumor models, regressions were seen at doses as low as 1/4 of the MTD (10 mg/kg, q4Dx3). The drug was also effective in mice bearing advanced systemic P388 leukemia, causing multi-log cell kill. In conclusion, SB-743921 has an impressive spectrum of activity in preclinical cancer models and is currently being evaluated in Phase I clinical trials.