TM5441 is an orally bioavailable PAI-1 inhibitor with an IC50 ranging from 13.9 to 51.1 μM, capable of inducing intrinsic apoptosis in various human cancer cell lines. TM5441 can alleviate cardiac hypertension and vascular senescence induced by Nω-nitro-l-arginine methyl ester[1][2]. TM5441 inhibits the proliferation of HT1080, HCT116, Daoy, MDA-MB-231, and Jurkat cells in a dose-dependent manner, with IC50 values ranging from 13.9 to 51.1 μM. It also dose-dependently increases caspase 3/7 activity in HT1080 and HCT116 cells. Furthermore, TM5441 enhances apoptosis in these cells and induces mitochondrial depolarization[1]. In mouse proximal tubular epithelial cells, TM5441 effectively inhibits the fibrosis and inflammatory marker mRNA expression induced by PAI-1, and reverses the inhibition of plasminogen activator activity induced by PAI-1[2].
TM5441 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HGPS fibroblasts
10 µM
10 days
TM5441 treatment restored the proliferative potential of HGPS human fibroblasts, mitigated senescence, and lowered DNA damage signaling.
Cell Death Dis. 2022 Aug 26;13(8):737
Mouse brain endothelial cells (bEnd.3)
10 µM
24 hours
TM5441 treatment enhanced angiogenic properties of bEnd.3 cells, as evidenced by increased total tube length, number of nodes, number of junctions, and number of meshes.
TM5441 treatment enhanced angiogenic properties of pMBMECs, as evidenced by increased total tube length, number of nodes, number of junctions, and number of meshes.
Mol Ther Nucleic Acids. 2023 Jan 2;31:276-292
HUVEC
50 µM
24 hours
To test the effect of TM5441 on endothelial cell branching, results showed that TM5441 significantly inhibited the branching of HUVEC.
PLoS One. 2015 Jul 24;10(7):e0133786
Mouse proximal tubular epithelial (mProx24) cells
10 µM
4 hours
Inhibited PAI-1-induced mRNA expression of fibrosis and inflammation markers and reversed PAI-1-induced inhibition of plasmin activity
PLoS One. 2016 Jun 3;11(6):e0157012
HCT116
9.7-60.3 µM (IC50)
48 hours
To test the effect of TM5441 on cell viability, results showed that TM5441 significantly reduced the viability of HCT116 cells.
PLoS One. 2015 Jul 24;10(7):e0133786
HT1080
9.7-60.3 µM (IC50)
48 hours
To test the effect of TM5441 on cell viability, results showed that TM5441 significantly reduced the viability of HT1080 cells.
PLoS One. 2015 Jul 24;10(7):e0133786
C2C12 myoblasts
0.5 µM
short-term and long-term treatment
TM5441 inhibits PAI-1, alleviates muscle atrophy, and improves survival rate in GBM patients after radiotherapy.
Cells. 2022 Oct 1;11(19):3102
TM5441 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Streptozotocin (STZ)-induced diabetic model
Oral
10 mg/kg/day
Once daily for 16 weeks
Evaluated the renoprotective effects of TM5441 in diabetic kidney injury, showing effective inhibition of albuminuria, mesangial expansion, ECM accumulation, and macrophage infiltration
PLoS One. 2016 Jun 3;11(6):e0157012
Mice
Kl/kl mice
Oral
100 mg/kg/day
Once daily
TM5441 prolonged the lifespan of kl/kl mice, reduced the expression of senescence markers, and preserved organ structure and function.
Proc Natl Acad Sci U S A. 2014 May 13;111(19):7090-5
Mice
High-fat diet-induced obesity model
Oral
15 mg/kg/day
Once daily for 35 days
TM5441 treatment significantly suppressed high-fat diet-induced body weight gain, improved leptin sensitivity, and upregulated thermogenesis-related gene expressions in brown adipose tissue.
Front Pharmacol. 2020 Jun 24;11:943
BALB/c athymic nude mice
GBM orthotopic xenograft model
Oral gavage
20 mg/kg
5 times
TM5441 inhibits PAI-1, alleviates muscle atrophy, and improves survival rate in GBM patients after radiotherapy.
Cells. 2022 Oct 1;11(19):3102
C57BL/6J mice
High-fat diet-induced obesity model
Oral gavage
20 mg/kg
Once daily for 10 weeks
TM5441 prevented HFD-induced body weight gain and systemic insulin resistance, and improved adipocyte function
Br J Pharmacol. 2016 Sep;173(17):2622-32
Mice
HT1080 and HCT116 xenograft models
Oral
20 mg/kg
Once daily for 16-30 days
To test the effect of TM5441 on tumor growth and vasculature, results showed that TM5441 increased tumor cell apoptosis and significantly disrupted tumor vasculature.
PLoS One. 2015 Jul 24;10(7):e0133786
C57BL/6J mice
L-NAME-induced hypertension and vascular senescence model
Oral
20 mg/kg/day
Daily administration for 8 weeks
TM5441 attenuated L-NAME-induced hypertension, cardiac hypertrophy, and periaortic fibrosis, and prevented the increase in vascular senescence markers p16Ink4a expression and telomere length shortening.
Circulation. 2013 Nov 19;128(21):2318-24
Mice
High-fat/high-cholesterol high-sugar (HFHS) diet or methionine- and choline-deficient (MCD) diet-induced steatohepatitis with fibrosis
Oral
20 mg/kg/day
Continued for 8 weeks (MCD diet) or 16 weeks (HFHS diet)
TM5441 effectively attenuates diet-induced obesity and hepatic steatosis but does not prevent NASH-related fibrosis in mice
Hepatol Commun. 2018 Sep 26;2(12):1479-1492
C57BL/6J mice
High-fat, high-sugar diet-induced obesity model
Dietary addition
20 mg/kg/day
Continued for 8 weeks
TM5441 significantly attenuated weight gain in obese mice, improved hepatic steatosis, and reduced adipose tissue inflammation.
Obesity (Silver Spring). 2021 Apr;29(4):713-720
Spontaneously hypertensive rats (SHR)
Middle cerebral artery occlusion (MCAO) model
Intravenous injection
5 mg/kg
Single dose, 10 minutes before reperfusion
TM5441 reduced acute brain injury volume in both young and aged SHR, increased collateral perfusion, and dilated leptomeningeal anastomotic arterioles (LMAs) through an NO-dependent mechanism.
Stroke. 2018 Aug;49(8):1969-1976
Mice (C57BL/6)
Middle cerebral artery occlusion (MCAO) model
Intravenous injection
5 mg/kg
Single dose, 15 minutes before reperfusion
TM5441 significantly increased cerebrovascular blood flow at the stroke-affected site, reduced brain injury, and improved functional recovery post-stroke.
Mol Ther Nucleic Acids. 2023 Jan 2;31:276-292
Rats
Spontaneously hypertensive rats (SHRs) and Wistar rats
Intravenous injection
5 mg/kg
10-minute infusion
TM5441 modestly increased cerebral blood flow (CBF) in SHRs but not in Wistar rats, and it did not have a beneficial effect on stroke outcomes.
Front Neurol. 2024 Mar 21;15:1373445
Mice
UM-HET3 mice
Oral
60 ppm
Starting at age 11 months
Evaluate the effect of TM5441 on lifespan, no significant effect observed
Aging Cell. 2019 Jun;18(3):e12953
TM5441 动物研究
Animal study
Oral administration of TM5441 at 20 mg/kg daily to mice with HT1080 and HCT116 xenografts increases apoptosis in tumor cells and significantly disrupts the tumor vasculature, thereby reducing tumor growth and improving survival rates. The average peak plasma concentration one hour after oral administration is 11.4 μM, with undetectable levels after 23 hours[1].
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