MI-2, a MALT1 inhibitor (IC50=5.84 μM), directly targets MALT1, irreversibly inhibiting its protease activity. This inhibition is associated with decreased NF-κB reporter activity, blocked c-REL nuclear translocation, and reduced expression of NF-κB-dependent genes. MI-2 is non-toxic to animals[1].
体内研究
The MALT1 inhibitor MI-2 (administered intraperitoneally at a dose of 25 mg/kg daily for 14 days) significantly inhibits the growth of both TMD8 and HBL-1 ABC-DLBCL xenografts.
体外研究
The MALT1 inhibitor MI-2 (1-1000 nM; 48 hours) specifically reduces the activity of MALT1-dependent DLBCL cell lines. The GI50 values of HBL-1, TMD8, OCI-Ly3, and OCI-Ly10 cells are 0.2, 0.5, 0.4, and 0.4 μM, respectively [1].
The MALT1 inhibitor MI-2 (62-1000 nM; 24 hours) induces a reduction in MALT1-mediated cleavage in a dose-dependent manner[1].
MALT1 inhibitor MI-2 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Monocytes
0.5 µM
12 days
MI-2 strongly suppressed the differentiation of monocytes into osteoclasts in the absence or presence of the inflammatory cytokine TNFα.
Sci Rep. 2017 Sep 19;7(1):11889.
U87 cells
0, 2, 4 µM
12 hours
To evaluate the effect of MI-2 on cell proliferation, the results showed that MI-2 significantly inhibited the proliferation of U87 cells.
J Cell Mol Med. 2020 Jul;24(13):7550-7562.
U251 cells
0, 2, 4 µM
12 hours
To evaluate the effect of MI-2 on cell proliferation, the results showed that MI-2 significantly inhibited the proliferation of U251 cells.
J Cell Mol Med. 2020 Jul;24(13):7550-7562.
MEC1 cells
0.2 µM
24 hours
MI-2 dose-dependently reduced the viability of MEC1 cells with an IC50 of 0.2 μM at 24 hours.
Cancer Res. 2017 Dec 15;77(24):7038-7048.
PBMCs from CLL patients
1.17 µM
24 hours
MI-2 induced dose-dependent cell death in PBMCs from CLL patients with a mean IC50 of 1.17 μM.
Cancer Res. 2017 Dec 15;77(24):7038-7048.
PBMCs from healthy volunteers
10 µM
24 hours
MI-2 significantly increased cell death in PBMCs from healthy volunteers at 10 μM concentration.
Cancer Res. 2017 Dec 15;77(24):7038-7048.
Aortic smooth muscle cells (SMCs)
0.1 µM, 1 µM, 2.5 µM, 5 µM, 10 µM
3 hours, 6 hours, 24 hours
MI-2 induced cell death in aortic SMCs, which was rescued by the iron chelator DFO or Fer-1 (a specific inhibitor of ferroptosis), but not by inhibitors of apoptosis, pyroptosis, or necrosis. MI-2 downregulated the expression of GPX4 and FTH1, activated autophagy, and reduced the cleavage of CYLD.
To evaluate the effect of MI-2 on the growth of multiple myeloma cells, results showed that MI-2 significantly inhibited cell growth and induced mitochondria-dependent apoptosis
Blood Adv. 2024 Aug 13;8(15):4003-4016.
Primary multiple myeloma cells (CD138+)
1.5 µM
48 hours
To evaluate the effect of MI-2 on primary multiple myeloma cells, results showed that MI-2 exerted strong cytotoxicity against CD138+ cells
Blood Adv. 2024 Aug 13;8(15):4003-4016.
Mouse and human aortic SMCs
1 µM
6 hours
MI-2 induced ferroptotic cell death in mouse and human aortic SMCs, increased intracellular iron levels, and disrupted mitochondrial structure.
Cell Death Discov. 2023 Dec 15;9(1):456.
B-ALL cell lines
50 mM
96 hours
To evaluate the killing effect of Z-VRPR-fmk on B-ALL cell lines, results showed significant reduction in cell viability
Haematologica. 2024 May 1;109(5):1348-1358.
MALT1 inhibitor MI-2 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
C57BL/6 mice
Intraperitoneal injection
0.05 to 25 mg/kg
Daily for 10 days
To evaluate the toxicity of MI-2 in mice, results showed that MI-2 was not significantly toxic to mice
Cancer Cell. 2012 Dec 11;22(6):812-24
C57BL/6 mice
Neointima formation model
Local application
10 μM
3 weeks
MI-2 significantly inhibited neointima formation in the carotid artery, and this effect was partially reversed by co-treatment with Fer-1.
Cell Death Discov. 2023 Dec 15;9(1):456.
NSG mice
T-ALL mouse model
Intraperitoneal injection
20 mg/kg
5 days per week for 4 weeks
MI-2 significantly prolonged the survival of T-ALL mouse model and reduced the leukemic burden.
Front Oncol. 2020 Sep 23;10:558339
C57BL/6 mice
GBM model
Intraperitoneal injection
20 mg/kg, 40 mg/kg
Daily until the end of the experiment
To evaluate the effect of MI-2 on tumor growth in vivo, the results showed that MI-2 significantly inhibited tumor growth and prolonged the survival of mice.
J Cell Mol Med. 2020 Jul;24(13):7550-7562.
NSG mice
Human multiple myeloma xenograft model
Intraperitoneal injection
25 mg/kg
5 days per week for 4 weeks
To evaluate the efficacy of MI-2 in a multiple myeloma xenograft model, results showed that MI-2 significantly prolonged survival and inhibited tumor growth
Blood Adv. 2024 Aug 13;8(15):4003-4016.
DBA/1 J mice
Collagen-induced arthritis model
Intraperitoneal injection
25 mg/kg
Once daily for 18 days
MI-2 significantly ameliorated pathologic bone erosion and synovitis in the collagen-induced arthritis model.
Sci Rep. 2017 Sep 19;7(1):11889.
Rats
Spinal cord ischemia/reperfusion injury model
Intraperitoneal injection
25 mg/kg/day
For three consecutive days
MI-2 alleviates spinal cord ischemia/reperfusion injury-induced blood-spinal cord barrier destruction and neuroinflammation by suppressing NF-κB-ERS signaling, thereby decreasing neuronal loss and protecting hindlimb motor function.
J Inflamm Res. 2021 Sep 2;14:4329-4345
Meat ducks
E. coli infection model
Intraperitoneal injection
30 mg/kg
Once daily for 14 days
To study the effect of MI-2 on bone metabolism in E. coli-infected meat ducks, the results showed that MI-2 treatment significantly reduced the levels of bone resorption markers TRAP and CTx and improved bone quality.
J Anim Sci Biotechnol. 2022 Aug 5;13(1):92
Mice
Bleomycin-induced pulmonary fibrosis model
Intraperitoneal injection
30 mg/kg
Once daily for 7 or 21 days
MI-2 reduced weight loss and mortality, decreased inflammatory cell infiltration, cytokine overexpression, and tissue injury, and modulated the excessive production of reactive oxygen species and inflammatory mediators induced by bleomycin. Additionally, MI-2 demonstrated anti-fibrotic activity by reducing TGF-β, α-SMA, and TRAF6 expression.
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