ML-210 is a prodrug that selectively inhibits GPX4 covalently with an EC50 of 30nM[1]. ML-210 has been widely used as a target or model compound to develop a range of GPX4 degraders[2].
In vitro, ML-210 treatment at 10μM for 2 hours induced rapid accumulation of lipid radicals in clear-cell renal cell carcinoma cells and caused ferroptosis[3]. Treatment of PANC-1 cells with 3μM ML-210 for 48 hours significantly inhibited cell viability, strongly decreased N-cadherin expression, increased lipid peroxides on the cell membrane, and inhibited cell migration[4]. ML-210 treatment (10μM) for 24h significantly induced cell cycle arrest in ABCB1 overexpressing colorectal cancer cells without altering ABCB1 protein expression[5]. In OCI-AML3 cells, treatment with 0.5µM of ML-210 for 48h simultaneously increased the proportion of annexin V-positive and DAPI-positive cells, resulting in an increased number of apoptotic cells[6].
In vivo, ML-210 treatment (5mg/kg; administered intraperitoneally every other day for 20 days) inhibited ovarian cancer progression and modestly reduced body weight in mice[7].
References:
[1] Eaton J K, Furst L, Ruberto R A, et al. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles[J]. Nature chemical biology, 2020, 16(5): 497-506.
[2] Wang H, Wang C, Li B, et al. Discovery of ML210-Based glutathione peroxidase 4 (GPX4) degrader inducing ferroptosis of human cancer cells[J]. European Journal of Medicinal Chemistry, 2023, 254: 115343.
[3] Zou Y, Palte M J, Deik A A, et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis[J]. Nature communications, 2019, 10(1): 1617.
[4] Takemura K, Ikeda K, Miyake H, et al. Epithelial–Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells[J]. Biomolecules, 2025, 15(1): 70.
[5] Li Y C, Xiong Y M, Long Z P, et al. ML210 Antagonizes ABCB1-Not ABCG2-Mediated Multidrug Resistance in Colorectal Cancer[J]. Biomedicines, 2025, 13(5): 1245.
[6] Akiyama H, Zhao R, Ostermann L B, et al. Mitochondrial regulation of GPX4 inhibition–mediated ferroptosis in acute myeloid leukemia[J]. Leukemia, 2024, 38(4): 729-740.
[7] Li N, Jiang X, Zhang Q, et al. Synergistic suppression of ovarian cancer by combining NRF2 and GPX4 inhibitors: in vitro and in vivo evidence[J]. Journal of Ovarian Research, 2024, 17(1): 49.
ML-210是一种前体药物，能够选择性共价抑制GPX4，EC50值为30nM[1]。ML-210已被广泛用作靶点或模型化合物来开发多种GPX4降解剂[2]。
在体外，10μM浓度的ML-210处理2小时可诱导透明细胞肾癌细胞中脂质自由基的快速积累并引发铁死亡[3]。用3μM浓度的ML-210处理PANC-1细胞48小时能显著抑制细胞活力，明显降低N-钙黏蛋白表达，增加细胞膜上的脂质过氧化物并抑制细胞迁移[4]。10μM浓度的ML-210处理24小时可在不改变ABCB1蛋白表达的情况下，显著诱导ABCB1过表达的结直肠癌细胞发生细胞周期阻滞[5]。在OCI-AML3细胞中，0.5µM浓度的ML-210处理48小时会同时增加膜联蛋白V阳性和DAPI阳性细胞比例，导致凋亡细胞数量上升[6]。
在体内，采用5mg/kg剂量的ML-210隔天腹腔注射给药持续20天，可抑制小鼠卵巢癌进展并轻微降低体重[7]。