product name OTS964
Description: OTS964 is a potent and selective TOPK inhibitor with high affinity and selectivity and IC50 value is 28 nM. OTS964 is a dimethylated derivative of OTS514. OTS964 can inhibit TOPK kinase activity with high affinity and selectivity. 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.
References: Sci Transl Med. 2014 Oct 22;6(259):259ra145.
465.44
Formula
C23H24N2O2S.2HCl
CAS No.
1338545-07-5 (HCl salt)
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 85 mg/mL (182.6 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
Synonyms
other peoduct :
| In Vitro |
In vitro activity: OTS964 inhibits the growth of TOPK-positive cells with low IC50 values [A549 (31 nM), LU-99 (7.6 nM), DU4475 (53 nM), MDAMB- 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)], whereas its growth inhibitory effect against TOPK-negative HT29 cancer cells is significantly weaker, with IC50 of 290nM. Although OTS964 reveals some suppressive effect on Src family kinases, the response to OTS964 in these cancer cells is not correlated with the expression of Src family kinases c-Src, Fyn, and Lyn, supporting the TOPK-dependent growth inhibitory effects of OTS964. Time lapse imaging in T47D cells shows that treatment with OTS964 induces cytokinesis defects followed by apoptosis. Kinase Assay: Cell Assay: Cells (100 μl, A549 cells, LU-99 cells, DU4475 cells, MDA-MB-231 cells, T47D cells, Daudi cells, UM-UC-3 cells, HCT-116 cells, MKN1 cells, MKN45 cells, HepG2 cells, MIAPaca-2 cells, 22Rv1 cells and HT29 cells) are plated in 96-well plates at a certain density. The cells are allowed to adhere overnight before exposure to compounds for 72 hours at 37°C. Plates are read with a spectrophotometer at a wavelength of 450 nm. All assays are carried out in triplicate. After measuring IC50 values, we calculates the z scores to produce P values. After log transformation (base 10) of IC50 values (nM), the mean and SD are calculated for the log values of the IC50 for the 13 TOPK-positive cell lines. |
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| In Vivo | Although administration of the free compound induces hematopoietic adverse reactions (leukocytopenia associated with thrombocytosis), the drug delivered in a liposomal formulation effectively causes complete regression of transplanted tumors without showing any adverse reactions in mice. Inhibition of TOPK activity with the liposomal OTS964 suppresses tumor growth through induction of cytokinesis defects and subsequent apoptosis. Although oral administration of OTS964 causes some hematopoietic toxicity, this is a transient effect. The spontaneous recovery from leukocytopenia is occured and the anticancer effectiveness of the oral drug is similar to that of the liposomal formulation, oral administration of the drug may prove to be more practical. |
| Animal model | BALB/cSLC-nu/nu mice |
| Formulation & Dosage | Dissolved in 5% glucose; 40 mg/kg; i.v. injection. |
| References | Sci Transl Med. 2014 Oct 22;6(259):259ra145. |
