亚硝基脂肪酸（NO2-FAs）是内源性生成的脂质信号介质，由共轭二烯脂肪酸与一氧化氮或亚硝酸衍生的活性物质之间的代谢和炎症反应形成。NO2-FAs与高反应性的蛋白质半胱氨酸硫醇可发生可逆的Michael加成反应，诱导蛋白质的翻译后修饰，从而影响蛋白质的功能。在本文中，我们报告了一种新的作用机制，即结构与(E) 10-硝基-顺-十八烯酸（CP-6）相似的天然和非天然硝基烯烃，最近通过临床前新药实验研究和1期和2期临床试验进行了风险评估，发现其通过抑制胸腺上皮样肿瘤的同源重组（HR）介导的DNA双链断裂（DSB）修复而诱导DNA损伤。CP-6特异性靶向在细胞中对RAD51控制的HR介导的DNA DSB修复中不可或缺的Cys319位点。硝基烯烃库筛选发现了两种结构不同的硝基烯烃，一种是非天然脂肪酸（E）8-硝基-酚十九烯酸（CP-8），另一种是二羧酸酯（二甲基硝基 - 辛-4 - 烯二酸酯（CP-23）），在TNBC细胞杀伤、与三种不同的聚(ADP-核糖)聚合酶（PARP）抑制剂和γ-IR的协同作用方面优于CP-6。CP-8和CP-23有效抑制了γ-IR诱导的RAD51灶形成和HR，但对良性人类上皮细胞或细胞周期相没有影响。在体内，CP-8和CP-23的功效有所不同，只有CP-8在HR敏感的TNBC小鼠模型中单独使用和与PARP抑制剂talazoparib联合使用时显示出有希望的抗癌活性。初步的临床前毒理学分析也表明CP-8是安全的，我们的数据支持CP-8作为一种新型的抗癌分子，用于治疗对同源重组介导的DNA修复抑制剂敏感的肿瘤。版权所有 © 2023. 由Elsevier B.V.出版。

Nitro fatty acids (NO2-FAs) are endogenously generated lipid signaling mediators from metabolic and inflammatory reactions between conjugated diene fatty acids and nitric oxide or nitrite-derived reactive species. NO2-FAs undergo reversible Michael addition with hyperreactive protein cysteine thiolates to induce posttranslational protein modifications that can impact protein function. Herein, we report a novel mechanism of action of natural and non-natural nitroalkenes structurally similar to (E) 10-nitro-octadec-9-enoic acid (CP-6), recently de-risked by preclinical Investigational New Drug-enabling studies and Phase 1 and Phase 2 clinical trials and found to induce DNA damage in a TNBC xenograft by inhibiting homologous-recombination (HR)-mediated repair of DNA double-strand breaks (DSB). CP-6 specifically targets Cys319, essential in RAD51-controlled HR-mediated DNA DSB repair in cells. A nitroalkene library screen identified two structurally different nitroalkenes, a non-natural fatty acid [(E) 8-nitro-nonadec-7-enoic acid (CP-8)] and a dicarboxylate ester [dimethyl (E)nitro-oct-4-enedioate (CP-23)] superior to CP-6 in TNBC cells killing, synergism with three different inhibitors of the poly ADP-ribose polymerase (PARP) and γ-IR. CP-8 and CP-23 effectively inhibited γ-IR-induced RAD51 foci formation and HR in a GFP-reported assay but did not affect benign human epithelial cells or cell cycle phases. In vivo, CP-8 and CP-23's efficacies diverged as only CP-8 showed promising anticancer activities alone and combined with the PARP inhibitor talazoparib in an HR-proficient TNBC mouse model. As preliminary preclinical toxicology analysis also suggests CP-8 as safe, our data endorse CP-8 as a novel anticancer molecule for treating cancers sensitive to homologous recombination-mediated DNA repair inhibitors.Copyright © 2023. Published by Elsevier B.V.