gpx4

GPX4-IN-4 (Compound 24) serves as a potent inhibitor of GPX4, applicable in cancer research [1].

GPX4-IN-6 is a small molecule covalent GPX4 inhibitor (IC50: 0.12 μM) with antitumour activity.GPX4-IN-6 induces ferroptosis and is used for the treatment= and prevention of triple negative breast cancer (TNBC).

GPX4-IN-5 is a small molecule covalent GPX4 inhibitor (IC50: 0.12 μM) with antitumour activity.GPX4-IN-5 induces ferroptosis and can be used for the prevention and treatment of triple-negative breast cancer (TNBC).

GPX4 24, a derivative of (1S,3R)-RSL3, acts as a potent inhibitor of glutathione peroxidase 4 (GPX4) through covalent binding in a concentration-dependent manner within 4T1 murine mammary carcinoma cells. This compound effectively induces ferroptosis in GPX4-dependent HT-1080 fibrosarcoma cells with an EC50 value of 0.16 µM. Additionally, at a dose of 200 mg/kg, GPX4 24 elevates malondialdehyde (MDA) levels in both kidney and plasma of mice, highlighting its impact on lipid peroxidation.

GPX4-IN-2 is a potent inhibitor of GPX4, exhibiting antiproliferative activity. It holds potential for cancer research applications.

GPX4-IN-3 (26a) is a potent inhibitor of glutathione peroxidase 4 (GPX4), selectively inducing ferroptosis. It demonstrates a 71.7% inhibition rate of GPX4 at a concentration of 1 μM [1].

PROTAC GPX4 Degrader-1 (DC-2) is a PROTAC-based compound that efficiently degrades GPX4, demonstrating a degradation concentration (DC 50) of 0.03 μM in HT1080 cells [1].

GPX4-IN-7 (Compound 31), an indirubin derivative, serves as a ferroptosis inducer in colon cancer treatment. Exhibiting potent antitumor properties, it inhibits HCT-116 cell growth with an IC50 of 0.49 μM. This compound also facilitates GPX4 degradation, leading to lipid ROS accumulation, thereby inducing ferroptosis [1].

PKUMDL-LC-101-D04 is a potent allosteric activator of glutathione peroxidase 4 (GPX4), a regulator of ferroptosis. GPX4 activity was increased to 150% of control levels when used at a concentration of 20 μM in a cell-free assay, and at a concentration of 61 μM in wild-type, but not Gpx4-/-, mouse embryonic fibroblast (MEF) extracts.PKUMDL-LC-101-D04 (200 μM) reduced cholesterol peroxide-induced MEF death.

JKE-1674 is an inhibitor of glutathione peroxidase 4 (GPX4). JKE-1674 is an active metabolite of the GPX4 inhibitor ML-210.

RSL3 (RSL3 1S) is an inhibitor of GPX4, and inhibits system xc- that blocks GSH synthesis (IC50=100 nM). RSL3 is a VDAC-independent activator of ferroptosis that is selective for tumor cells carrying oncogenic RAS.

iFSP1, a potent, selective, and glutathione-independent ferroptosis suppressor protein 1 (FSP1) (AIFM2) inhibitor with an EC50 of 103 nM, sensitizes diverse human cancer cell lines to ferroptosis inducers like (1S,3R)-RSL3. It uniquely triggers ferroptosis in GPX4-knockout cells overexpressing FSP1.

ML162 is an inhibitor of GPX4 that is selectively lethal to mutant RAS oncogene-expressing cell lines (IC50s = 25 and 578 nM for HRASG12V-expressing and wild-type BJ fibroblasts, respectively)

FINO2 is a potent ferroptosis-inducing compound that inhibits GPX4 activity. It functions as a stable oxidant, effectively oxidizing ferrous iron and demonstrating stability across varying pH levels. Furthermore, FINO2 induces widespread lipid peroxidation.

ML-210 (CID 49766530) is a selective RAS and covalent glutathione peroxidase 4 (GPX4) inhibitor(GPX4, EC50 : 30 nM), with anti-cancer activity

FIN56 is a specific inducer of ferroptosis.

1-Stearoyl-2-15(S)-HpETE-sn-glycero-3-PE is a phospholipid that contains stearic acid at the sn-1 position and 15(S)-HpETE at the sn-2 position. It is produced via oxidation of 1-stearoyl-2-arachidonoyl-sn-glycero-3-PE by 15-lipoxygenase (15-LO). 1-Stearoyl-2-15(S)-HpETE-sn-glycero-3-PE (0.6 and 0.9 μM) increases ferroptotic cell death in wild-type and Acsl4 knockout Pfa1 mouse embryonic fibroblasts (MEFs) treated with the GPX4 inhibitor RSL3.

Anticancer agent 154 (Compound 8h) enhances reactive oxygen species production, causing mitochondrial damage, and promotes cell apoptosis and DNA damage. It triggers ferroptosis by depleting GSH, diminishing GPX4 expression, and escalating lipid peroxidation. Furthermore, it effectively suppresses the proliferation of various cancer cells (HT29, H1975, A549, and MCF-7) with IC50 values ranging from 1.0 to 1.9 μM [1].

RC363 is an inhibitor of ferroptosis and a derivative of the antioxidant and hypocholesterolemic agent probucol .1It reduces 2,2-diphenyl-1-picrylhydrazyl radicals by approximately 40% in a cell-free assay when used at a concentration of 25 μM. RC363 prevents glutamate-induced toxicity in HT22 cultured hippocampal cells (IC50= 234.5 nM) but does not reduce oxidant levels in these cells. It increases the levels of glutathione peroxidase 1 (GPX1) and the activity of GPX in glutamate-challenged HT22 cells when used at a concentration of 3 μM. RC363 inhibits ferroptosis induced by the GPX4 inhibitor RSL3 in HT22 cells (IC50= 173.6 nM). 1.Bueno, D.C., Canto, R.F.S., de Souza, V., et al.New probucol analogues inhibit ferroptosis, improve mitochondrial parameters, and induce glutathione peroxidase in HT22 cellsMol. Neurobiol.57(8)3273-3290(2020)

N6F11 is a novel, selective and potent inducer of ferroptosis with anticancer and antitumour activity that promotes GPX4 degradation by binding to TRIM25 in cancer cells.N6F11 can be used to study pancreatic cancer.

NPD4928 enhanced the sensitivity of various cancer cells to GPX4 inhibitors, suggesting that the combination might have therapeutic potential via the induction of ferroptosis.

QD-394 is an inducer of reactive oxygen species (ROS) production.1It induces lipid peroxidation, increases in intracellular accumulation of reactive oxygen species (ROS), and decreases in the reduced glutathione (GSH) to oxidized GSH (GSSG) ratio in MIA PaCa-2 pancreatic cancer cells when used at concentrations ranging from 0.5 to 10 μM. QD-394 is cytotoxic to MIA PaCa-2, PANC-1, and BxPC-3 cancer cells (IC50s = 0.64, 0.34, and 0.9 μM, respectively). QD-394 acts synergistically with napabucasin to reduce colony formation in MIA PaCa-2 cells. 1.Hu, S., Sechi, M., Singh, P.K., et al.A novel redox modulator induces a GPX4-mediated cell death that is dependent on iron and reactive oxygen speciesJ. Med. Chem.63(17)9838-9855(2020)

Lepadin E, a notably cytotoxic compound, effectively stimulates ferroptosis via the canonical p53-SLC7A11-GPX4 pathway. By elevating p53 and repressing SLC7A11 and GPX4 expression, it heightens ROS and lipid peroxidation while also augmenting ACSL4 expression, culminating in cell death. This compound exhibits a considerable antitumor effect [1].

Lepadin H, a marine alkaloid and ferroptosis inducer, exhibits significant cytotoxicity by promoting p53 expression, escalating ROS production, and enhancing lipid peroxidation. It simultaneously decreases SLC7A11 and GPX4 levels while upregulating ACSL4 expression, thereby inducing ferroptosis via the p53-SLC7A11-GPX4 pathway [1].

icFSP1, an inhibitor of ferroptosis suppressor protein 1 (FSP1), promotes condensation and phase separation of FSP1 in cellular environments at 2.5 µM concentration but does not affect FSP1's enzymatic function in cell-free assessments (IC50 = > 30 µM). This compound selectively induces ferroptosis in HT-1080 fibrosarcoma cells in a dose-dependent manner. Furthermore, in vivo studies show that icFSP1 administered at 50 mg/kg significantly reduces both the volume and weight of tumors in a B16/F10 murine melanoma model utilizing human FSP1-overexpressing, Gpx4-/-Fsp1-/- B16/F10 cells.

BCP-T.A is an ferroptosis inducer that acts by binding to GPX4.

RC574 is an inhibitor of ferroptosis and a derivative of the antioxidant and hypocholesterolemic agent probucol .1It inhibits glutamate-induced cell death in HT22 cells (IC50= 276.2 nM) and mouse primary cortical neurons when used at a concentration of 3 μM. RC574 (3 μM) increases glutathione peroxidase 1 (GPX1) levels and GPX activity, as well as inhibits glutamate-induced mitochondrial superoxide anion production, in HT22 cells. It completely inhibits ferroptosis induced by the GPX4 inhibitor RSL3 in HT22 cells when used at concentrations ranging from 62.5 to 1,000 nM. 1.Bueno, D.C., Canto, R.F.S., de Souza, V., et al.New probucol analogues inhibit ferroptosis, improve mitochondrial parameters, and induce glutathione peroxidase in HT22 cellsMol. Neurobiol.57(8)3273-3290(2020)

NC-R17, an RSL3-based noncovalent GPX4 degrader implicated in ferroptosis, demonstrates anti-tumor activity and is utilized in the design of noncovalent GPX4-targeted proteolysis targeting chimeras (PROTACs) [1].

Gingerenone A is an effective Nrf2-Gpx4 activator. It is a small molecule compound isolated from ginger. It has anti-cancer activity, can prolong the cell cycle of cancer cells, and can inhibit dextran sodium sulfate (DSS)-induced colitis. Ferroptosis in secondary liver injury (SLI) in mice.

JKE-1716 is an inhibitor of glutathione peroxidase 4 (GPX4) and a derivative of the GPX4 inhibitor ML-210 .1JKE-1716 reduces viability of LOX-IMVI cancer cells in a concentration-dependent manner and in a panel of additional cancer cell lines, an effect that can be blocked by the ferroptosis inhibitor ferrostatin-1 . 1.Eaton, J.K., Furst, L., Ruberto, R.A., et al.Selective covalent targeting of GPX4 using masked nitrile-oxide electrophilesNat. Chem. Biol.16(5)497-506(2020)