DMX-5804 is a potent, orally active and selective MAP4K4 inhibitor with an IC50 value of 3 nM and a pIC50 of 8.55 against human MAP4K4, and weakly against MINK1/MAP4K6 (pIC50, 8.18) and TNIK/MAP4K7 (pIC50, 7.96). DMX-5804 enhances the cardiac function in mice. DMX-5804 increases the survival of mouse cardiomyocytes and attenuates ischaemia-reperfusion injury[1].
DMX-5804 细胞实验
Cell Line
Concentration
Treated Time
Description
References
vascular smooth muscle cells (VSMCs)
10 μmol/L
24 hours
Inhibition of MAP4K4 activity, restoration of VSMC contractility and morphological abnormalities
Commun Biol. 2022 Oct 7;5(1):1071
Human cardiac microvascular endothelial cells (HCMECs)
5–15 μM
72 hours
DMX-5804 significantly reduced SNO-Drp1, decreased Drp1 phosphorylation at Ser616, increased Drp1 phosphorylation at Ser637, and inhibited Drp1 translocation to mitochondria after HG/FFA treatment. Additionally, DMX-5804 ameliorated oxidative stress and ferroptosis induced by HG/FFA.
Cardiovasc Diabetol. 2024 May 9;23(1):164
vCor.4U cardiomyocytes
10 μM
24 hours
To evaluate the protective effect of DMX-5804 against oxidative stress-induced cell death, showing significant protection.
Cell Stem Cell. 2019 Apr 4;24(4):579-591. e12
human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs)
500 nM
suppresses cell death from oxidative stress
Basic Res Cardiol. 2021 May 20;116(1):34
DMX-5804 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Myocardial ischemia-reperfusion injury model
Oral
50 mg/kg
Two doses, spaced 10 hours apart
To validate the protective effect of DMX-5804 in vivo against myocardial ischemia-reperfusion injury, showing significant reduction in infarct size.
Cell Stem Cell. 2019 Apr 4;24(4):579-591. e12
Mouse
Myocardial infarction model
Oral
oral dosing
Reduced infarct size
Basic Res Cardiol. 2021 May 20;116(1):34
Mice
VSMC-specific RhoA conditional knockout mice
Intravenous injection
2.5 mg/kg
Three times per week for 4 weeks
Inhibition of MAP4K4 activity, reduction of AAA formation, restoration of vascular contractility and morphological abnormalities
Commun Biol. 2022 Oct 7;5(1):1071
Mice
Db/db mice
Oral
3 mg/kg
Three times per week for 24 weeks
DMX-5804 significantly abrogated SNO-Drp1, suppressed Drp1 phosphorylation at Ser616, and inhibited the mitochondrial translocation of Drp1 in db/db mice. Furthermore, DMX-5804 improved cardiac microvascular perfusion, stimulated angiogenesis, enhanced endothelial barrier function, and suppressed endothelial-associated inflammation.
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