GPX4 (glutathione peroxidase 4) is a selenoprotein that plays a critical role in protecting cells from lipid peroxidation and ferroptosis by reducing lipid hydroperoxides to their corresponding lipid alcohols. It is unique in its ability to reduce complex lipid hydroperoxides. ML210 is a selective covalent inhibitor of cellular GPX4 with an EC50 value of 0.04 μM. It exhibits a pattern of cell killing across 821 cancer cell lines. Furthermore, ML210 may be a prodrug that undergoes chemical transformation in cells to covalently modify GPX4. Treatment of cells with ML210 (10 μM, 90 min) led to accumulation of lipid hydroperoxides in LOX-IMVI cells[1]. Moreover, ML-210 has IC50 values of 71, 107 and 272 nM for BJeLR (HRASV12), DRD and BJeH-LT (without HRASV12) cell lines, respectively[2].
作用机制
In cells, ML210 reacts with cysteine and glutathione to form +434 Da ML210-GPX4 adduct[1].
ML-210 细胞实验
Cell Line
Concentration
Treated Time
Description
References
LNCaP
2 μM
ML210 significantly increased ROS levels in LNCaP cells and significantly inhibited the proliferation of LNCaP cells.
Cell Death Dis. 2024 Aug 3;15(8):559.
C4-2
2 μM
ML210 significantly increased ROS levels in C4-2 cells and significantly inhibited the proliferation of C4-2 cells.
Cell Death Dis. 2024 Aug 3;15(8):559.
LOX-IMVI cells
10 μM
90 min
To assess the effect of ML-210 on lipid peroxidation, results showed that ML-210 treatment led to the accumulation of lipid hydroperoxides.
Nat Chem Biol. 2020 May;16(5):497-506.
HCC4006 cells
10 μM
1 h
To assess the effect of ML-210 on GPX4 thermal stability using CETSA, results showed that ML-210 stabilized GPX4.
Nat Chem Biol. 2020 May;16(5):497-506.
LOX-IMVI cells
10 μM
1 h
To assess protein modification by ML-210 using fluorescent labeling, results showed that the ML-210-yne probe modified fewer proteins.
Nat Chem Biol. 2020 May;16(5):497-506.
SH-SY5Y cells
8.33 μM
24 h
Differentiated SH-SY5Y cells exhibited higher sensitivity to ML210-induced ferroptosis compared to parental cells.
Nature. 2020 Sep;585(7826):603-608.
SKOV3
1 μM
24 h
ML-210 treatment increased intracellular ROS levels, indicating it may inhibit cancer cells by inducing oxidative stress.
Cancer Res. 2021 Jan 15;81(2):384-399.
OVCAR5
2 μM
24 h
ML-210 treatment increased intracellular ROS levels, indicating it may inhibit cancer cells by inducing oxidative stress.
Cancer Res. 2021 Jan 15;81(2):384-399.
A549 ACLY/ACSS2-DKO cells
2 μM
48 h
To evaluate the sensitivity of ACLY/ACSS2-DKO cells to ferroptosis induced by ML-210, results showed that ACLY/ACSS2-DKO cells were more sensitive to ML-210-induced ferroptosis.
Sci Adv. 2023 May 3;9(18):eadf0138.
OVCAR-8
1 μM
3.5 h
To assess the effect of ML-210 on lipid peroxidation in OVCAR-8 cells, results showed that MMD KO cells had lower lipid peroxidation compared to control cells.
Cell Rep. 2023 Sep 26;42(9):113023.
786-O
0.25 μM
3.5 h
To assess the effect of ML-210 on lipid peroxidation in 786-O cells, results showed that MMD KO cells had lower lipid peroxidation compared to control cells.
Cell Rep. 2023 Sep 26;42(9):113023.
786-O
0.01953–20 μM
48–72 h
Validate GPX4 inhibition-induced cell death
Nat Commun. 2019 Apr 8;10(1):1617.
769-P
0.01953–20 μM
48–72 h
Validate GPX4 inhibition-induced cell death
Nat Commun. 2019 Apr 8;10(1):1617.
OS-RC2
0.01953–20 μM
48–72 h
Validate GPX4 inhibition-induced cell death
Nat Commun. 2019 Apr 8;10(1):1617.
RCC10RGB
0.01953–20 μM
48–72 h
Validate GPX4 inhibition-induced cell death
Nat Commun. 2019 Apr 8;10(1):1617.
ML-210 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Male BALB/c nude mice
A375 cell xenograft model
Subcutaneous injection
50 mg/kg
Every two days, for 20 days
ML210 triggered lipid peroxidation in vivo and synergized with MβCD to inhibit tumor growth
Redox Biol. 2023 Jun;62:102678
SCID mice
Prostate cancer xenograft model
Intraperitoneal injection
5 mg/kg
Daily for 33 days
ML210 combined with enzalutamide significantly inhibited tumor growth and increased H2O2 levels in tumors.
Cell Death Dis. 2024 Aug 3;15(8):559.
SCID mice
Not specified
Oral
50 mg/kg
Single dose, over 24 hours
To assess the pharmacokinetic properties of JKE-1674, results showed that the plasma concentration of JKE-1674 varied over time.
Nat Chem Biol. 2020 May;16(5):497-506.
Nude mice
786-O xenograft model
Subcutaneous injection
20 mg/kg
Once daily for 10 days
Validate the anti-tumor effect of GPX4 inhibition in vivo
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