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OTS-514 is a novel TOPK(PDZ binding kinase; PBK) inhibitor,IC50:2.6nM. The compound can inhibit TOPK kinase activity. TOPK (T-lymphokine-activated killer cell-originated protein kinase) is a protein that is found in a wide range of human cancers and is believed to work as an oncogene, promoting tumor growth.The enzyme shows highly elevated expression in several cancers including lymphomas, breast cancer and lung cancer. Its activity peaks in the M phase of the cell-division cycle, during which it phosphorylates several proteins involved in cancer cell cytokinesis, such as histone H3, protein regulator of cytokinesis 1 (PRC1), G protein signaling modulator 2 (GPSM2) and valosin containing protein.Many cancer cells upregulate TOPK and require its activity to drive their rapidly progressing cell cycles. Because the kinase is either not expressed or expressed at relatively low levels in most healthy tissues, targeting it in cancer cells could eliminate some of the risks associated with other cytokinesis enzymes.
It has been reported that OTS514 strongly inhibited the growth of the TOPK-positive cancer cell lines with low IC50 values ranging from 1.5 to 14 nM. While in HT29 cells, in which TOPK expression was little detectable, the IC50 value was 170 nM. Intravenous administration of free OTS514 at 1, 2.5, and 5mg/kg once a day for 2 weeks resulted in tumor growth Inhibition（TGI）of 5.7, 43.3, and 65.3% on day 15, respectively, without anybody weight loss. However, this inhibition also cause dysfunction in the differentiation process of hematopoietic stemcells (HSCs) to WBCs and RBCs but may enhance the differentiation of HSCs to megakaryocytes and platelets.
The antitumor effect of OTS514 in lung cancer xenograft model of LU-99 cells has also been investigated. OTS514 was administered to mice bearing LU-99 cancer cells after the tumor size reached about 200mm3. 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. However, the antitumor effect of OTS514 against LU-99 xenograft caused a significant reduction of WBCs.
For the detailed information of OTS514, the solubility of OTS514 in water, the solubility of OTS514 in DMSO, the solubility of OTS514 in PBS buffer, the animal experiment (test) of OTS514, the cell expriment (test) of OTS514, the in vivo, in vitro and clinical trial test of OTS514, the EC50, IC50,and affinity,of OTS514, For the detailed information of OTS514, the solubility of OTS514 in water, the solubility of OTS514 in DMSO, the solubility of OTS514 in PBS buffer, the animal experiment (test) of OTS514, the cell expriment (test) of OTS514, the in vivo, in vitro and clinical trial test of OTS514, the EC50, IC50,and affinity,of OTS514, Please contact DC Chemicals. |
