LPA (lysophosphatidic acid), which has been shown to be involved in certain diseases such as atherosclerosis and cancer, can act through its receptor like LPA receptor 1, LPA receptor 2, or LPA receptor 3 and elicit different biological actions, like Ca2+ mobilization, changing in cAMP accumulation, changing cell shape and motility, and cell proliferation. Ki16425 is a LPA receptor antagonist with Ki values of 0.34μM for mouse LPA receptor 1 and 0.93μM for human LPA receptor 3, but with much higher Ki value for human LPA receptor 2 (Ki=6.5μM). Pre-treatment with 1μM Ki16425 can inhibit LPA-induced [Ca22+]i increase in THP-1 cells and 3T3 fibroblasts. Also, Ki16425 could decrease the This LPA-induced response of inositol phosphate production in 3T3 fibroblasts and A431 cells, but not S1P3- or S1P2-expressing CHO cells, at concentration of 10μM. The cAMP accumulation inhibited by LPA in FRTL-5 thyroid cells in a PTX-sensitive manner could be almost completely suppressed by 10μM Ki16425. Cell proliferation and migration induced by LPA in Swiss 3T3 fibroblasts could be inhibited dose-dependently by Ki16425. Treatment with Ki16425 at dose of 10mg/kg intradermally could improve dermal and lung fibrosis in a mouse model of bleomycin-induced murine scleroderma. Pre-treatment with 10μM for 30 minutes could completely block LPA-induced YAP/TAZ phosphorylation and inhibit Hippo signaling pathway in HEK293A cells.
作用机制
Ki16425 can antagonize the binding of LPA to the receptor, thus competitively inhibiting LPA-induced GTP binding and LPA receptor binding to membrane fractions.[1]
Ki16425 细胞实验
Cell Line
Concentration
Treated Time
Description
References
PC-3M-luc-C6 cells
1 µM
12 hours
Ki16425 completely inhibited LPA-induced migration of PC-3M-luc-C6 cells
Exp Mol Med. 2014 Jul 4;46(7):e104.
Cardiomyocytes
1 µM
1-5 days
To evaluate the effect of LPA on cardiomyocyte proliferation, results showed that LPA induced cardiomyocyte proliferation in a time- and concentration-dependent manner
Theranostics. 2020 Aug 29;10(24):10892-10907.
786-O cells
1 µM
30 minutes
Ki16425 effectively attenuated LPA-induced cell signaling and invasion
Clin Cancer Res. 2013 Dec 1;19(23):6461-72.
UMRC3 cells
1 µM
30 minutes
Ki16425 effectively attenuated LPA-induced cell signaling and invasion
Clin Cancer Res. 2013 Dec 1;19(23):6461-72.
Cardiomyocytes
1, 5, 10 µM
48 hours
To evaluate the effect of different concentrations of LPA on cardiomyocyte proliferation, results showed that LPA increased the number of EdU-positive cardiomyocytes in a concentration-dependent manner
Theranostics. 2020 Aug 29;10(24):10892-10907.
Human primary valve interstitial cells
1 µM
7 days
Ki16425 negated platelet-induced mineralization of VIC cultures
Eur Heart J. 2019 May 1;40(17):1362-1373.
Valve interstitial cells (VICs)
10 µM
7 days
Ki16425 prevented OxLDL-induced mineralization of VICs
Cardiovasc Res. 2017 Sep 1;113(11):1351-1363.
Mouse Embryo Fibroblast (MEF)
10 µM
Ki16425 completely blocked AOCP-induced MEF cell migration, indicating that LPA is the major component in AOCP responsible for inducing MEF cell migration.
Exp Mol Med. 2008 Aug 31;40(4):445-52.
4T1 cells
60 nM
Debio-0719 had little antiproliferative effect on 4T1 cells but inhibited their motility.
J Natl Cancer Inst. 2012 Sep 5;104(17):1306-19.
MDA-MB-231T cells
60 nM
Debio-0719 inhibited the migration ability of MDA-MB-231T cells.
J Natl Cancer Inst. 2012 Sep 5;104(17):1306-19.
MDA-BO2/GFP cells
0-10 µM
Ki16425 dose-dependently inhibited LPA-induced proliferation of MDA-BO2/GFP cells.
Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9643-8.
CHO/H92523wt cells
0-10 µM
Ki16425 dose-dependently inhibited LPA-induced proliferation of CHO/H92523wt cells.
Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9643-8.
Ki16425 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
LPA-induced hydrocephalus model
Intracranial injection
1 mg/kg
Single injection, 15 minutes before LPA injection
Pretreatment with Ki16425 resulted in 44% of animals exhibiting no VM, but this reduction was not statistically significant from controls.
Sci Adv. 2019 Oct 9;5(10):eaax2011
Mice
Experimental Autoimmune Encephalomyelitis (EAE) model
Intraperitoneal injection
15 and 30 mg/kg
Once daily until the end of the experiment
Ki16425 significantly deteriorated motor disability in EAE mice, increased spinal cord demyelination, inflammation, cellular infiltration, and blood-brain barrier disruption. The underlying mechanism was associated with the overproduction of reactive oxygen species (ROS) via NOX2 and NOX3.
J Neuroinflammation. 2021 Oct 19;18(1):240
Mice
4T1 spontaneous metastasis model
Subcutaneous injection
15 mg/kg
Twice daily, continued until the end of the experiment
Debio-0719 significantly inhibited the metastasis of 4T1 cells to the liver and lungs but had no effect on primary tumor size.
J Natl Cancer Inst. 2012 Sep 5;104(17):1306-19.
SD rats
Myocardial infarction model
Intraperitoneal injection
20 mg/kg
Daily from the day of birth
To evaluate the effect of Ki16425 on cardiomyocyte proliferation, results showed that Ki16425 significantly reduced the number of pH3-, BrdU- and Ki67-positive cardiomyocytes
Theranostics. 2020 Aug 29;10(24):10892-10907.
BALB/c Nude mice
RCC xenograft models
Subcutaneously
20 mg/kg
Once daily for 48 days
Ki16425 markedly inhibited RCC tumor growth and reduced tumor proliferation and angiogenesis
Clin Cancer Res. 2013 Dec 1;19(23):6461-72.
NMRI nu/nu mice
Breast cancer bone metastasis model
Subcutaneous injection
20 mg/kg
Once daily for 16 days
Ki16425 significantly inhibited the progression of bone metastasis, reducing bone destruction and tumor burden.
Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9643-8.
Mice
LDLR-/-apoB100/100IGFII transgenic mice
Intraperitoneal injection
5 mg/kg/day
Once daily for 5 weeks
Ki16425 abrogated platelet-induced progression of aortic valve calcification
Eur Heart J. 2019 May 1;40(17):1362-1373.
Mice
LDLR-/-/ApoB100/100/IGFII transgenic mice
Intraperitoneal injection
5 mg/kg/day
Once daily for 3 months
Ki16425 reduced the progression rate of CAVS and decreased hydroxyapatite deposition in aortic valve leaflets
Antagonist activity at human recombinant LPA1 receptor expressed in CHOK1 cells assessed as inhibition of lysophosphatidic acid-induced intracellular calcium influx, IC50=0.51 μM
17467986
HEK293 cells
Function assay
5 mins
Antagonist activity at human LPA1 receptor expressed in HEK293 cells assessed as inhibition of LPA-induced AP-TGF-alpha release treated 5 mins before LPA addition measured after 60 mins
22658556
human chem1 cells
Function assay
Antagonist activity at LPA1 expressed in human chem1 cells assessed as effect on intracellular calcium mobilization by FLIPR assay, IC50=0.046 μM
20056548
PC-3 cells
Function assay
Binding affinity for Lysophosphatidic acid receptor in PC-3 cells, Ki=1.74 μM
16033271
rat hepatic stellate cells
Function assay
Antagonist activity at LPA1 receptor in rat hepatic stellate cells assessed as inhibition of lysophosphatidic acid-induced intracellular calcium influx, IC50=0.16 μM
17467986
RH7777 rat hepatoma cells
Function assay
Binding affinity for Lysophosphatidic acid receptor 3 expressed in RH7777 rat hepatoma cells, Ki=0.148 μM
16033271
RH7777 rat hepatoma cells
Function assay
Inhibition of LPA-induced calcium transients in RH7777 rat hepatoma cells expressing LPA3 receptor, IC50=0.301 μM
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