生物活性

• 靶点	TOPK IC50:28nM

• 描述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. OTS-964 is a potent TOPK inhibitor with high affinity and selectivity for TOPK kinase with IC₅₀ value of 28 nM. OTS964 (2 μM) could inhibit 79.7% of TOPK activity, whereas the mean and the SD of the inhibitory effects against other kinases were 18.5 and 24.6%, respectively. OTS964 inhibited the growth of TOPK-positive cells with low IC₅₀ values [A549 (31 nM), LU-99 (7.6 nM), DU4475 (53 nM), MDA-MB-231 (73 nM), T47D (72 nM), Daudi (25 nM), UM-UC-3 (32 nM), HCT-116 (33 nM), MKN1 (38 nM), MKN45 (39 nM), HepG2 (19 nM), MIAPaca-2 (30 nM), and 22Rv1 (50 nM)]. In mice bearing LU-99 lung cancer cells, a TGI (tumor growth inhibition) of 44% was observed on day 22 without any body weight loss after intravenous treatment of OTS964 at 40 mg/kg. A TGI of 110% was observed on day 22 after treatment of liposomal OTS964 at 40 mg/kg. The U-99 xenograft mice were intravenously treated with liposomal OTS964 (40 mg/kg) or vehicle at days 1, 4, 8, and 11, and tumors were collected on day 12. Treatment with OTS964 significantly increased the number of LU-99 cells with the “intercellular bridge” (P < 0.0001), which is one of the markers indicating impaired cell division. The oral administration of free OTS964 at 50 or 100 mg/kg once every day for 2 weeks resulted in TGIs of 79 and 113% on day 15, respectively, without any body weight loss in LU-99 xenograft model^[2].