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. OTS514 is an extremely potent TOPK inhibitor. The compound inhibited TOPK kinase activity with a median inhibitory concentration (IC50) value of 2.6 nM. After a 2-hour incubation with 0.2 μM OTS514, the highest inhibition was observed for TOPK (83.5% inhibition) out of a panel of 60 diverse human protein kinases indicating the specificity of the TOPK inhibitory effect of this compound. 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 resulted in TGI (tumor growth inhibition) of 5.7, 43.3, and 65.3% on day 15, respectively, without any body weight loss. Further, a significant increase in the megakaryocyte population was observed after treatment with 20 or 40 nM OTS514 (P = 0.04 and P = 0.02, respectively). Moreover, OTS514 was administered to mice bearing LU-99 cancer cells after the tumor size reached about 200 mm3. 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[2].
OTS514 细胞实验
Cell Line
Concentration
Treated Time
Description
References
SW48
20 nM
24 hours
Inhibited cell proliferation and induced apoptosis
Front Pharmacol. 2022 Jan 18;12:772926
LoVo
20 nM
48 hours
Inhibited cell proliferation and induced apoptosis
Front Pharmacol. 2022 Jan 18;12:772926
HCT116
20 nM
48 hours
Inhibited cell proliferation and induced apoptosis
Front Pharmacol. 2022 Jan 18;12:772926
HaCaT cells
5 nM, 10 nM, 20 nM
12 hours
Inhibited TOPK activity and reduced the expression of neutrophil chemokines CXCL1, CXCL2, and CXCL8
Cell Commun Signal. 2024 Aug 1;22(1):386
CH22 cells
1, 2, 5, 10 nM
2, 3, 5 days
To evaluate the effect of OTS514 on chordoma cell growth and proliferation. Results showed that OTS514 decreased cell viability in a dose- and time-dependent manner in UCH2 and CH22 cells, with IC50 values of 1.36-46.29 and 0.50-2.79 nmol/L, respectively.
Cell Prolif. 2020 Oct;53(10):e12901
UCH2 cells
1, 2, 5, 10 nM
2, 3, 5 days
To evaluate the effect of OTS514 on chordoma cell growth and proliferation. Results showed that OTS514 decreased cell viability in a dose- and time-dependent manner in UCH2 and CH22 cells, with IC50 values of 1.36-46.29 and 0.50-2.79 nmol/L, respectively.
Cell Prolif. 2020 Oct;53(10):e12901
U2OS
6.25, 12.5, 25, 50 nM
2, 3, or 5 days
To evaluate the inhibitory effect of OTS514 on osteosarcoma cell proliferation. Results showed that OTS514 significantly reduced the viability of KHOS and U2OS cells in a dose- and time-dependent manner, with IC50 values of 4.77–21.17 nM and 6.34–42.10 nM after 5 days of treatment, respectively.
Mol Oncol. 2021 Dec;15(12):3721-3737
KHOS
6.25, 12.5, 25, 50 nM
2, 3, or 5 days
To evaluate the inhibitory effect of OTS514 on osteosarcoma cell proliferation. Results showed that OTS514 significantly reduced the viability of KHOS and U2OS cells in a dose- and time-dependent manner, with IC50 values of 4.77–21.17 nM and 6.34–42.10 nM after 5 days of treatment, respectively.
Mol Oncol. 2021 Dec;15(12):3721-3737
HAP1-TOPK k.o. cells
100 nM
30 minutes prior to TOPKi-NBD
Validate the specificity of TOPKi-NBD in non-TOPK-expressing cells
Eur J Nucl Med Mol Imaging. 2020 Apr;47(4):1003-1010
H446
10 or 20 nM
48 hours
Evaluate the growth-suppressive effect of OTS514 on SCLC cells, showing that OTS514 reduced TOPK protein levels in a dose-dependent manner
Cancer Sci. 2017 Mar;108(3):488-496
H69AR
10 or 20 nM
48 hours
Evaluate the growth-suppressive effect of OTS514 on SCLC cells, showing that OTS514 reduced TOPK protein levels in a dose-dependent manner
Cancer Sci. 2017 Mar;108(3):488-496
DMS114
10 or 20 nM
48 hours
Evaluate the growth-suppressive effect of OTS514 on SCLC cells, showing that OTS514 reduced TOPK protein levels in a dose-dependent manner
Cancer Sci. 2017 Mar;108(3):488-496
SKOV3
20, 50, 100 nM
48 hours
OTS514 significantly inhibited ovarian cancer cell proliferation and enhanced the lethal effect of cisplatin.
Cell Death Dis. 2019 Feb 18;10(3):166
A2780
20, 50, 100 nM
48 hours
OTS514 significantly inhibited ovarian cancer cell proliferation and enhanced the lethal effect of cisplatin.
Cell Death Dis. 2019 Feb 18;10(3):166
H2171
42.6 nM (IC50)
72 hours
Evaluate the growth-suppressive effect of OTS514 on suspension SCLC cells, showing weaker effects on cells with low TOPK expression
Cancer Sci. 2017 Mar;108(3):488-496
H146
39.3 nM (IC50)
72 hours
Evaluate the growth-suppressive effect of OTS514 on suspension SCLC cells, showing weaker effects on cells with low TOPK expression
Cancer Sci. 2017 Mar;108(3):488-496
H524
2.6 nM (IC50)
72 hours
Evaluate the growth-suppressive effect of OTS514 on suspension SCLC cells, showing stronger effects on cells with high TOPK expression
Cancer Sci. 2017 Mar;108(3):488-496
H82
7.2 nM (IC50)
72 hours
Evaluate the growth-suppressive effect of OTS514 on suspension SCLC cells, showing stronger effects on cells with high TOPK expression
Cancer Sci. 2017 Mar;108(3):488-496
H69
0.4 nM (IC50)
72 hours
Evaluate the growth-suppressive effect of OTS514 on suspension SCLC cells, showing stronger effects on cells with high TOPK expression
Cancer Sci. 2017 Mar;108(3):488-496
OTS514 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
IMQ-induced psoriasis-like dermatitis model
Topical application
100mg (dorsal skin) and 20mg (ear skin)
Once daily for 5 days
Alleviated already-established psoriasis-like dermatitis symptoms, including erythema, scaling, and epidermal thickening
Cell Commun Signal. 2024 Aug 1;22(1):386
Nude mice
KRASG12C A549 xenograft model
Intraperitoneal injection
2.5 mg/kg
Twice a week for 4 weeks
OTS514 enhanced the anticancer effect of 5-FU, and the combination with AMG510 showed synergistic anti-tumor effects
J Cell Mol Med. 2023 Jun;27(12):1637-1652
BALB/c nude mice
Ovarian cancer xenograft model
Oral
25 mg/kg
Once daily for 15 days
OTS514 significantly enhanced the growth inhibitory effect of cisplatin on ovarian cancer xenograft models.
Cell Death Dis. 2019 Feb 18;10(3):166
Nude mice
HCT116 colorectal cancer xenograft model
Intravenous injection
50 μg/mouse
Single injection, analyzed after 5 hours
Evaluate tumor-specific uptake of TOPKi-NBD in vivo
Eur J Nucl Med Mol Imaging. 2020 Apr;47(4):1003-1010
搜索
