Sphingosine kinases (SphKs) catalyze the conversion of the sphingosine to the promitogenic/migratory product, sphingosine-1-phosphate (S1P). SphK/S1P pathway has been linked to the progression of cancer and various other diseases including allergic inflammatory disease, cardiovascular diseases, rejection after transplantation, the central nervous system, and virus infections[1]. Gene-targeted mice null for the sphingosine kinase 1 isoform whose hearts are subjected to ischemia/reperfusion injury exhibit increased infarct size and respond poorly either to ischemic preconditioning or to ischemic postconditioning[2]. SphK2 is a nuclear protein that suppresses cell proliferation by inhibiting DNA synthesis, while also enhancing apoptosis in diverse cell types. Genetic inhibition of SphK2 did not significantly impact the severity or progression of inflammatory arthritis, while pharmacologic inhibition of SphK2 led to significantly more severe arthritis[3]. SphK2 is involved in regulating interleukin (IL)-12/interferon gamma (IFN-γ) and histone deacetylase-1/2 (HDAC-1/2) signalling and, potentially, retinoid-related orphan receptor gamma t (ROR-γt) stability linked with T helper (Th) 17 cell polarisation[4]. K145 inhibited the activity of SphK2 in a dose-dependent manner with an IC50 of 4.30 uM. The Lineweaver-Burk analysis revealed a Ki of 6.4±0.7 uM for SphK2 and indicated that K145 is a substrate competitive inhibitor (with sphingosine). K145 accumulates in U937 cells, suppresses the S1P level, and inhibits SphK2. K145 also exhibited inhibitory effects on the growth of U937 cells as well as apoptotic effects in U937 cells, and that these effects may be through the inhibition of downstream ERK and Akt signaling pathways[5].
K145 HCl 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MCF-7 cells
1 µM
2 days
K-145 reduced nuclear S1P, almost completely blocked H3-K9ac, HIF1α associated spheroid formation, and enhanced dead cells
FASEB J. 2020 Mar;34(3):4293-4310.
A172
5 µM
24 hours
K145 significantly inhibited TRIM22 overexpression-induced proliferation of GBM cells
Exp Mol Med. 2023 Jun;55(6):1203-1217.
U251MG
5 µM
24 hours
K145 significantly inhibited TRIM22 overexpression-induced proliferation of GBM cells
Exp Mol Med. 2023 Jun;55(6):1203-1217.
K145 HCl 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NOD/SCID/IL-2Rγ−/− (NSG) mice
5TGM1.BR myeloma model
Intraperitoneal injection
20mg/kg
K145 six days a week, bortezomib three times a week for 17 days
Evaluate combination therapy of K145 with bortezomib
Neoplasia. 2022;24(1):1-11.
NOD/SCID mice
GBM xenograft model
Intraperitoneal injection
50 mg/kg
Once daily until the end of the experiment
K145 significantly inhibited TRIM22 overexpression-induced proliferation of GBM cells and increased the survival rate of mice
Exp Mol Med. 2023 Jun;55(6):1203-1217.
NSG mice
TNBC MDA-MB-231 xenograft model
Intraperitoneal injection
30 mg/kg
35 days
In the K-145 treatment group, the mean volume of the MDA-MB-231 tumors in the treated mice had a reduced tumor volume >50% compared to vehicle-treated mice. Tumor weights of K-145-treated mice were also significantly less than that of vehicle-treated mice. S1P and dihydro-S1P levels in the tumor tissue nuclei were significantly reduced in the treated group compared to the vehicle group. H3-K9ac, HIF-1α, and HIF-2α levels were decreased in the K145-treated tumor samples compared to the vehicle controls. K145-treated tumors have significantly decreased HIFα-target genes VEGFA and SERPINE1 mRNA compared to the vehicle controls
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