Tunable Cysteine-Targeting Electrophilic Heteroaromatic Warheads Induce Ferroptosis.

ABSTRACT: 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 by 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. The 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, th

SUBMITTER: Karaj E 

PROVIDER: S-EPMC10408038 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature