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].
OTS964 HCl 细胞实验
Cell Line
Concentration
Treated Time
Description
References
A375 cells
100 nM
12 days
evaluating the cytotoxic effect of OTS964 on A375 cells
Structure. 2022 Dec 1;30(12):1615-1625.e4.
HFL-1
200 nM
4-hour pretreatment, washed off after 24 hours
To evaluate the radiosensitizing effect of OTS964 on PC3 cells, showing SER10 of 1.34 (P<0.001).
Br J Cancer. 2017 Aug 8;117(4):503-512.
MRC5
200 nM
4-hour pretreatment, washed off after 24 hours
To evaluate the radiosensitizing effect of OTS964 on SQ20B cells, showing SER10 of 1.54 (P=0.003).
Br J Cancer. 2017 Aug 8;117(4):503-512.
DU145
70 nM
4-hour pretreatment, washed off after 24 hours
To evaluate the radiosensitizing effect of OTS964 on DU145 cells, showing SER10 of 1.42 (P<0.001).
Br J Cancer. 2017 Aug 8;117(4):503-512.
HeLa
100 nM
4-hour pretreatment, washed off after 24 hours
To evaluate the radiosensitizing effect of OTS964 on HeLa cells, showing SER10 of 2.14 (P<0.001).
Br J Cancer. 2017 Aug 8;117(4):503-512.
HCT116
70 nM
4-hour pretreatment, washed off after 24 hours
To evaluate the radiosensitizing effect of OTS964 on HCT116 cells, showing SER10 of 1.40 (P<0.001).
Br J Cancer. 2017 Aug 8;117(4):503-512.
HUVEC cells
128 ng/mL
72 hours
Assess the toxicity of OTS964 on healthy cells, showing no significant toxicity
Pharmaceutics. 2022 Jul 18;14(7):1488.
DLD-1 cells
1 μM
8 hours
Inhibited mRNA splicing
Eur J Med Chem. 2022 Aug 5;238:114433.
MIA PaCa-2 cells
100 nM
72 hours
Inhibited cell proliferation
Eur J Med Chem. 2022 Aug 5;238:114433.
A375 cells
100 nM
10 hours
Induced G2/M cell cycle arrest
Eur J Med Chem. 2022 Aug 5;238:114433.
Calu-6 lung cancer cells
20 nM
24 hours
To evaluate the radiosensitizing effect of OTS964 on Calu-6 cells, results showed that OTS964 significantly increased radiosensitivity.
Cell Death Differ. 2021 Apr;28(4):1333-1346.
H460 lung cancer cells
20 nM
24 hours
To evaluate the radiosensitizing effect of OTS964 on H460 cells, results showed that OTS964 significantly increased radiosensitivity.
Cell Death Differ. 2021 Apr;28(4):1333-1346.
B16F0 cells
64 ng/mL
24 hours
Evaluate the cytotoxicity of OTS964 on B16F0 cells, showing significant inhibition of cell growth
Pharmaceutics. 2022 Jul 18;14(7):1488.
OTS964 HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
B16F0 tumor model
Intraperitoneal injection
1 mg/kg
Every 2 days, total 3 times
Evaluate the antitumor effect of OTS964 in vivo, showing significant tumor growth inhibition
Pharmaceutics. 2022 Jul 18;14(7):1488.
CD-1 nude mice
H460 and Calu-6 lung cancer xenograft models
Intraperitoneal injection
20 mg/kg
Administered on days 0 and 2
To evaluate the effect of OTS964 in combination with fractionated radiotherapy, results showed that OTS964 significantly delayed tumor growth.
搜索
