Tunable Cysteine-Targeting Electrophilic Hetero-Aromatic Warheads Induce Ferroptosis

• Published in: Journal of medicinal chemistry 2022-08, Vol.65 (17), p.11788-11817
• Main Authors: Karaj, Endri, Sindi, Shaimaa H., Kuganesan, Nishanth, Perera, Lalith, Taylor, William, Viranga Tillekeratne, L. M.
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c00909

Once considered potential liabilities, the modern era witnesses a renaissance of interest in covalent inhibitors in drug discovery. The available toolbox of electrophilic warheads is limited with constraints on tuning reactivity and selectivity. Following our work on a class of ferroptotic agents termed CETZOLEs, we discovered new tunable heterocyclic electrophiles which are capable of inducing ferroptosis. Biological evaluation demonstrated that thiazoles with an alkyne electrophile at the 2-position selectively induce ferroptosis with high potency. Density functional theory calculations and NMR kinetic studies demonstrated the ability of our heterocycles to undergo thiol addition, an apparent prerequisite for cytotoxicity. Chemoproteomic analysis indicated several potential targets, the most prominent among them being GPX4 protein. These results were further validated by western blot analysis and Cellular Thermal Shift Assay. Incorporation of these heterocycles into appropriate pharmacophores generated highly cytotoxic agents such as the analog BCP-T.A, with low nM IC 50 values in ferroptosis-sensitive cell lines.