Tunable Cysteine-Targeting Electrophilic Heteroaromatic Warheads Induce Ferroptosis.
Tunable Cysteine-Targeting Electrophilic Heteroaromatic Warheads Induce Ferroptosis.
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DOI：
10.1021/acs.jmedchem.2c00909
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发表时间：
2022-09-08
影响因子：
7.3
通讯作者：
Tillekeratne LMV
中科院分区：
文献类型：
--
作者：
Karaj E;Sindi SH;Kuganesan N;Perera L;Taylor W;Tillekeratne LMV
曾经被认为是潜在的责任，现代时代见证了对共价抑制剂在药物发现中的兴趣复兴。可用的亲电弹头工具箱受到调整反应性和选择性的限制。继我们对一类被称为CETZOLEs的致铁剂的研究之后，我们发现了新的可调杂环亲电试剂，它能够诱导致铁。生物学评价表明，在2位具有炔亲电性的噻唑类药物可选择性地高效诱导铁下垂。密度泛函理论计算和核磁共振动力学研究表明，我们的杂环具有巯基加成的能力，这显然是细胞毒性的先决条件。化学蛋白质组学分析发现了几个潜在的靶点，其中最突出的是GPX4蛋白。这些结果通过western blot分析和细胞热移实验进一步验证。将这些杂环结合到适当的药物载体中产生高细胞毒性药物，如类似物BCP-T。A，在嗜铁中毒敏感细胞系中具有低nM IC50值。
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 IC50 values in ferroptosis-sensitive cell lines.
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影响因子：
5.2
作者：
Alhamadsheh, MM;Hudson, RA;Tillekeratne, LMV
通讯作者：
Tillekeratne, LMV
影响因子：
10.6
作者：
Forman, Henry Jay;Zhang, Hongqiao;Rinna, Alessandra
通讯作者：
Rinna, Alessandra
影响因子：
2.7
作者：
Eaton JK;Furst L;Cai LL;Viswanathan VS;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
4.8
作者：
Burmeister, Cora;Lueersen, Kai;Liebau, Eva
通讯作者：
Liebau, Eva