Imidazole ketone erastin (IKE) is an inducer of ferroptosis, and it is also a potent, selective, and metabolically stable inhibitor of the cystine-glutamate antiporter, system Xc-. Dramatic improvement of the half-maximal inhibitory constants for system xc− inhibition was observed for IKE (IC50 = 30 nM), compared to erastin and PE. In a diffuse large B cell lymphoma (DLBCL) xenograft model, IKE exerted an antitumor effect by inhibiting system xc-, leading to glutathione depletion, lipid peroxidation, and the induction of ferroptosis biomarkers.
|Cell lines||DLBCL cell line|
|Preparation method||DLBCL cells are plated at 10,000 cells per well in white 384-well plates (32 μL per well) in technical duplicates and incubated overnight. The cells are then treated with 8 μL medium containing a two-fold dilution series of vehicle (DMSO), IKE (starting from 100 μM) with or without Fer-1 (starting from 200 μM). After 24 h incubation, 40 μL of 50% CellTiter-Glo / 50% cell culture medium is added to each well and incubated at room temperature with shaking for 15 min. Luminescence is measured. All cell viability data are normalized to the DMSO vehicle condition. Experiments are performed three independent times with different passages for each cell line. From these data, dose-response curves and IC50 values are computed.|
|Incubation time||24 h|
|Animal models||Non-obese diabetic/ severe combined immunodeficiency (NOD/SCID) mice|
|Formulation||dissolved in 5% DMSO/95% HBSS at pH 4 solution|
|Dosages||50 mg/kg, 17 mg/kg|
|Administration||IP and PO and IV|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||DMSO 90 mg/mL|
Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model
Yan Zhang, et al. Cell Chem Biol. 2019 May 16;26(5):623-633.e9. PMID: 30799221.
Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility
Marie-Helene Larraufie, et al. Bioorg Med Chem Lett. 2015 Nov 1;25(21):4787-4792. PMID: 26231156.
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