Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, Toledo, Ohio 43606, United States.
Department of Biological Sciences, College of Natural Sciences and Mathematics, University of Toledo, Toledo, Ohio 43606, United States.
J Med Chem. 2022 Sep 8;65(17):11788-11817. doi: 10.1021/acs.jmedchem.2c00909. Epub 2022 Aug 19.
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, the most prominent among them being GPX4 protein. These results were further validated by western blot analysis and the cellular thermal shift assay. Incorporation of these heterocycles into appropriate pharmacophores generated highly cytotoxic agents such as the analogue , with low nM IC values in ferroptosis-sensitive cell lines.
曾被视为潜在缺陷的共价抑制剂，在药物研发领域迎来了复兴。可用的亲电弹头工具包受到反应性和选择性调节的限制。在我们研究一类被称为 CETZOLE 的铁死亡诱导剂之后，我们发现了新的可调节杂环亲电试剂，它们能够诱导铁死亡。生物学评估表明，在 2 位具有炔烃亲电试剂的噻唑选择性地以高活性诱导铁死亡。密度泛函理论计算和 NMR 动力学研究表明，我们的杂环能够进行硫醇加成，这是细胞毒性的明显前提。化学蛋白质组学分析表明了几个潜在的靶标，其中最突出的是 GPX4 蛋白。这些结果通过 Western blot 分析和细胞热转移测定进一步得到了验证。将这些杂环纳入适当的药效团中，生成了高度细胞毒性的试剂，如类似物 ，在铁死亡敏感细胞系中的低 nM IC 值。
