Biological Activity
OTS514 is a highly potent TOPK inhibitor, which inhibits TOPK kinase activity with a median inhibitory concentration (IC50) value of 2.6 nM.
In Vitro
To confirm the specificity of OTS514 against TOPK, a panel of 60 diverse human protein kinases is used. The activity of each kinase is measured after a 2 hour incubation with 0.2 μM OTS514. The highest inhibition is observed for TOPK (83.5% inhibition), whereas the mean and the SD of the inhibitory effects against other kinases are 11.5 and 18.5%, respectively, indicating the specificity of the TOPK inhibitory effect of OTS514. TOPK expression is examined in cancer cell lines derived from various cancer types, such as lung cancer (A549, LU-99), breast cancer (DU4475, MDA-MB-231, and T47D), Burkitt lymphoma (Daudi), bladder cancer (UM-UC-3), colon cancer (HCT-116 and HT29), gastric cancer (MKN1 and MKN45), liver cancer (HepG2), pancreatic cancer (MIAPaca-2), and prostate cancer (22Rv1). High expression of TOPK is observed in all of these cell lines except HT29. The growth inhibitory effects of OTS514 are examined ton each cell line and strong growth inhibitory effects are found with low IC50 values ranging from 1.5 to 14 nM for the TOPK-positive cancer cell lines. On the other hand, the IC50 value for HT29 cells, in which TOPK expression is hardly detectable, is significantly higher at 170 nM (P=5.92×10-11).[1].
In Vivo
The in vivo antitumor effect of OTS514 is first investigated t 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 results in tumor growth inhibition (TGI) of 5.7, 43.3, and 65.3% on day 15, respectively, without any body weight loss. The antitumor effect of OTS514 is further investigated in another lung cancer xenograft model of LU-99 cells. Intravenous administration of OTS514 (5 mg/kg) once a day for 2 weeks achieve good growth-suppressive effect with TGI of 104% without any body weight loss. However, although the antitumor effect against LU-99 xenograft is stronger than that against A549 xenograft, the treatment still causes a significant reduction of white blood cells (WBCs) (P<0.01)[1].
References & source
Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.
