OTSSP167 inhibits the growth of A549 (lung), T47D (breast), DU4475 (breast), 22Rv1 (prostate) and HT1197 (bladder) cancer cells with IC50 values of 6.7, 4.3, 2.3, 6.0 and 97 nM, respectively[1]. OTSSP167 effectively interferes with the mitotic checkpoint and disrupts MCC and MCC-APC/C interactions in MCF7 cells, also causing GFP-MELK localization to the cell cortex in prometaphase cells[2]. As a selective MELK inhibitor, OTSSP167 exhibits a strong in vitro activity with an IC50 of 0.41 nM[3].
体内研究
In vivo, OTSSP167 at 20 mg/kg (i.v.) achieves a tumor growth inhibition (TGI) of 73% in a xenograft mouse model; oral administrations at 1, 5, and 10 mg/kg result in TGI of 51, 91, and 108%, respectively, though a 20 mg/kg oral dose does not suppress tumor growth in PC-14 xenografts[1].
体外研究
OTSSP167 inhibits the growth of A549 (lung), T47D (breast), DU4475 (breast), 22Rv1 (prostate) and HT1197 (bladder) cancer cells with IC50 values of 6.7, 4.3, 2.3, 6.0 and 97 nM, respectively[1].
OTSSP167 effectively interferes with the mitotic checkpoint and disrupts MCC and MCC-APC/C interactions in MCF7 cells, also causing GFP-MELK localization to the cell cortex in prometaphase cells[2].
As a selective MELK inhibitor, OTSSP167 exhibits a strong in vitro activity with an IC50 of 0.41 nM[3].
作用机制
OTSSP167 optimally occupies the active site of MELK, especially the hydrophobic back pocket, mainly through van der Waals interactions.[2]
OTSSP167 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HEK293T cells
100 nM
48 hours
Evaluate the inhibitory effect of OTS167 on DYRK1A
Bioorg Med Chem. 2020 Jan 1;28(1):115193.
C4-2b cells
30 nM
2 hours
To evaluate the inhibitory effect of OTS167 on MELK activity, results showed that OTS167 inhibited phosphorylation of the known MELK substrate ACC at nanomolar concentrations.
EMBO Mol Med. 2018 Mar;10(3):e8274.
Primary human FLT3 mutant AML blast mononuclear cells
50 nM
24 hours
OTS167 downregulates FLT3 protein expression in primary human FLT3 mutant AML cells.
Blood Cancer J. 2021 Mar 3;11(3):48.
THP-1
50 nM
24 hours
OTS167 downregulates FLT3 protein expression in FLT3 wild-type AML cell lines.
Blood Cancer J. 2021 Mar 3;11(3):48.
SK-N-BE2
0 to 8 nM
24 hours
To evaluate the effects of OTS167 on cell cycle. Results showed that OTS167 at 8 nM significantly decreased the number of cells in G1 phase and increased the number of cells in S phase.
Mol Cancer Ther. 2019 Mar;18(3):507-516.
SW13
0.625 nM, 1.25 nM
24-48 hours
To evaluate the effect of OTS167 on SW13 cell proliferation, results showed that OTS167 had antiproliferative and cytotoxic effects at nanomolar concentrations.
Evaluation of intestinal UGTs' contribution to OTS167 metabolism, observing OTS167-G formation
Drug Metab Dispos. 2015 Jul;43(7):928-35.
R7T1 β-cells
5-40 nM
48 hours
Assess the induction of human β-cell replication by OTS167
Bioorg Med Chem. 2020 Jan 1;28(1):115193.
LNCaP cells
30 nM
48 hours
To evaluate the effect of OTS167 on apoptosis, results showed that OTS167 increased the fraction of apoptotic cells.
EMBO Mol Med. 2018 Mar;10(3):e8274.
NCI-H295R
1.25 nM, 2.5 nM
48-72 hours
To evaluate the effect of OTS167 on NCI-H295R cell proliferation, results showed that OTS167 had antiproliferative and cytotoxic effects at nanomolar concentrations.
J Exp Clin Cancer Res. 2022 Sep 23;41(1):282.
PBMC
10 nM
6 days
Evaluate the effect of OTS167 on PBMC cells, results showed OTS167 reduced the number of CD138+ cells.
Blood Cancer J. 2016 Aug 19;6(8):e460.
Patient-derived primary ovarian cancer cells
0, 1, 10, 40, 100 nM
72 hours
To evaluate the growth inhibitory effect of OTS167 on patient-derived primary ovarian cancer cells, results showed significant growth inhibition at concentrations of 10, 40, and 100 nM.
To evaluate the cytotoxic effect of OTS167 on ovarian cancer cell lines, results showed significant growth inhibition in all tested cell lines.
J Gynecol Oncol. 2020 Nov;31(6):e93.
KMS-34 CFZ
12.25 nM (IC50)
72 hours
Evaluate the effect of OTS167 on KMS-34 CFZ cell viability, results showed OTS167 had comparable effects on the resistant subclone KMS-34 CFZ.
Blood Cancer J. 2016 Aug 19;6(8):e460.
8226 Dox40
60.59 nM (IC50)
72 hours
Evaluate the effect of OTS167 on 8226 Dox40 cell viability, results showed 8226 Dox40 cells were the most resistant to OTS167.
Blood Cancer J. 2016 Aug 19;6(8):e460.
MM1R
12.08 nM (IC50)
72 hours
Evaluate the effect of OTS167 on MM1R cell viability, results showed OTS167 had comparable effects on the resistant subclone MM1R.
Blood Cancer J. 2016 Aug 19;6(8):e460.
U266
18.47 nM (IC50)
72 hours
Evaluate the effect of OTS167 on U266 cell viability, results showed OTS167 decreased cell viability in a dose-dependent manner.
Blood Cancer J. 2016 Aug 19;6(8):e460.
MM1S
7.911 nM (IC50)
72 hours
Evaluate the effect of OTS167 on MM1S cell viability, results showed OTS167 decreased cell viability in a dose-dependent manner.
Blood Cancer J. 2016 Aug 19;6(8):e460.
SK-N-DZ
0 to 1 µM
72 hours
To evaluate the effects of OTS167 on neuroblastoma cell proliferation. Results showed that OTS167 inhibited the proliferation of neuroblastoma cells with high MELK expression at low nM concentrations.
To evaluate the cytotoxic effect of OTS167 on ovarian cancer cell lines, results showed significant growth inhibition in all tested cell lines.
J Gynecol Oncol. 2020 Nov;31(6):e93.
MOLM:14
50 nM
8-24 hours
OTS167 downregulates FLT3 protein expression in FLT3 mutant AML cell lines.
Blood Cancer J. 2021 Mar 3;11(3):48.
MV4:11
50 nM
8-24 hours
OTS167 downregulates FLT3 protein expression in FLT3 mutant AML cell lines.
Blood Cancer J. 2021 Mar 3;11(3):48.
OTSSP167 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nuþ /Nuþ mice
Human ACC xenograft model
Intraperitoneal injection
10 mg/kg
Daily (Monday-Friday) for five weeks
To evaluate the antitumor efficacy of OTS167 in mice with human ACC xenografts, results showed that OTS167 significantly reduced tumor burden.
J Exp Clin Cancer Res. 2022 Sep 23;41(1):282.
NOD scid gamma mice
C4-2b xenograft model
Intraperitoneal injection
10 mg/kg
Daily, for the duration of the experiment
To evaluate the inhibitory effect of OTS167 on tumor growth, results showed that OTS167 significantly reduced tumor growth and induced apoptosis of tumor cells.
EMBO Mol Med. 2018 Mar;10(3):e8274.
Female nude mice
Neuroblastoma xenograft model
Intraperitoneal injection
10 mg/kg
Twice per week for 3 weeks
To evaluate the inhibitory effects of OTS167 on neuroblastoma xenograft growth. Results showed that OTS167 significantly inhibited tumor growth, with the average tumor weight in the treatment group being 77% lower than that in the control group.
Mol Cancer Ther. 2019 Mar;18(3):507-516.
NOD.Cg PrkdcscidIL2rgtm1Wjl/SzJ (NSG) mice
FLT3 mutant AML xenograft mouse model
Oral gavage
5-10 mg/kg
5 days treated/2 days off schedule
OTS167 in combination with TKIs results in prolonged survival in a FLT3 mutant AML xenograft mouse model.
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