TOPK (T-lymphokine-activated killer cell-originated protein kinase) is highly and frequently transactivated in various cancer tissues, including lung and triple-negative breast cancers, and plays an indispensable role in the mitosis of cancer cells. OTS514 is an extremely potent TOPK inhibitor. The compound inhibited TOPK kinase activity with a median inhibitory concentration (IC50) value of 2.6 nM. After a 2-hour incubation with 0.2 μM OTS514, the highest inhibition was observed for TOPK (83.5% inhibition) out of a panel of 60 diverse human protein kinases indicating the specificity of the TOPK inhibitory effect of this compound. In a xenograft model of A549 cells (TOPK-positive lung cancer cells), intravenous administration of free OTS514 at 1, 2.5, and 5 mg/kg once a day for 2 weeks resulted in TGI (tumor growth inhibition) of 5.7, 43.3, and 65.3% on day 15, respectively, without any body weight loss. Further, a significant increase in the megakaryocyte population was observed after treatment with 20 or 40 nM OTS514 (P = 0.04 and P = 0.02, respectively). Moreover, OTS514 was administered to mice bearing LU-99 cancer cells after the tumor size reached about 200 mm3. Intravenous administration of OTS514 (5 mg/kg) once a day for 2 weeks achieved good growth-suppressive effect with TGI of 104% without any body weight loss[2].
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