SCH 2047069, a Novel Oral Kinesin Spindle Protein Inhibitor, Shows Single-Agent Antitumor Activity and Enhances the Efficacy of Chemotherapeutics

Abstract

Kinesin spindle protein (KSP) is a mitotic kinesin required for the formation of the bipolar mitotic spindle, and inhibition of this motor protein results in mitotic arrest and cell death. KSP inhibitors show preclinical antitumor activity and are currently undergoing testing in clinical trials. These agents have been dosed intravenously using various dosing schedules. We sought to identify a KSP inhibitor that could be delivered orally and thus provide convenience of dosing as well as the ability to achieve more continuous exposure via the use of dose-dense administration. We discovered SCH 2047069, a potent KSP inhibitor with oral bioavailability across species and the ability to cross the blood-brain barrier. The compound induces mitotic arrest characterized by a monaster spindle and is associated with an increase in histone H3 and mitotic protein monoclonal 2 phosphorylation both in vitro and in vivo. SCH 2047069 showed antitumor activity in a variety of preclinical models as a single agent and in combination with paclitaxel, gemcitabine, or vincristine.

Kinesin Spindle Protein (KSP) Inhibitors in Combination with Chemotherapeutic Agents for Cancer Therapy

“…The anticancer mechanism of vincristine is binding to tubulin dimers and inhibiting the assembly of the microtubule structures, which leads to mitotic arrest in the metaphase 78. The thiadiazole derivative SCH2047069, used as a KSP inhibitor, exhibited potent antitumor activity against leukemia, lymphoma, ovarian, and colon tumors, both in vitro and in vivo 36. In A2780 tumor cell lines, SCH2047069 dosed orally weekly at 10 mg kg −1 only resulted in 41 % tumor growth inhibition (TGI) 36.…”

“…The thiadiazole derivative SCH2047069, used as a KSP inhibitor, exhibited potent antitumor activity against leukemia, lymphoma, ovarian, and colon tumors, both in vitro and in vivo 36. In A2780 tumor cell lines, SCH2047069 dosed orally weekly at 10 mg kg −1 only resulted in 41 % tumor growth inhibition (TGI) 36. Conversely, the trial investigating the effects of combining SCH2047069 with vincristine demonstrated a significant enhancement of activity (76 % TGI).…”

“…The suppression of microtubule dynamics and prolonged activation of the mitotic checkpoint triggers apoptosis or reversion to the G phase of the cell cycle without cell division 85. The combination of SCH2047069 and paclitaxel resulted in a significant enhancement of activity (98 % TGI) relative to the 43 % TGI observed with paclitaxel used as a single agent 36. The investigation evaluating CRx‐026 with paclitaxel in A549 NSCLC cells indicated a strong synergy relative to the results in tumors treated with either CRx‐026 or paclitaxel alone 67.…”

“…Basso et al. evaluated the combination of a single dose of gemcitabine (100 mg kg −1 intraperitoneally) and SCH2047069 on a q3d schedule (days 0, 3, 6, and 9) 36. As single agents, gemcitabine and SCH2047069 were observed to produce 80 and 74 % TGI, respectively.…”

Impaired angiogenesis and tumor development by inhibition of the mitotic kinesin Eg5

“…First evidence that kinesin inhibition might be explored as a new anti-cancer strategy came in 2004 [10] and chemical inhibitors of Eg5 have been designed and tested with success against solid tumors in preclinical tumor models [11]. Consequently, there are increasing numbers of clinical trials investigating the efficacy of Eg5 inhibitors alone or associated with classical chemotherapy in hematological and solid malignancies [12].…”