School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou 510006, China.
J Med Chem. 2022 Sep 22;65(18):12346-12366. doi: 10.1021/acs.jmedchem.2c01058. Epub 2022 Sep 2.
The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (). Among the new compounds, with the potent HDAC inhibitory and G4 stabilizing activity could induce more DNA G4 formation than SAHA and in TNBC cells. Remarkably, caused more G4-related DNA damage and G4-related differentially expressed genes, consistent with its effect on disrupting the cell cycle, invasion, and glycolysis. Furthermore, significantly suppresses the proliferation of various TNBC cells and the MDA-MB-231 xenograft model without evident toxicity. Our study suggests a novel strategy for TNBC therapeutics through dual-targeting HDAC and G4.
三阴性乳腺癌（TNBC）的发展与 G-四链体（G4）高度相关；因此，靶向 G4 是治疗 TNBC 的一种潜在策略。由于同时抑制组蛋白去乙酰化酶（HDAC）可以增强 G4 靶向化合物的作用，我们通过将 HDAC 抑制剂的锌结合药效团连接到 G4 靶向的异吲哚酮支架（）上，设计并合成了两类新型 G4/HDAC 双重靶向化合物。在新化合物中，具有强效 HDAC 抑制和 G4 稳定活性的化合物 能够诱导 TNBC 细胞中更多的 DNA G4 形成，其效果强于 SAHA 和 。值得注意的是，化合物 能够引起更多的 G4 相关 DNA 损伤和 G4 相关差异表达基因，这与其破坏细胞周期、侵袭和糖酵解的作用一致。此外，化合物 能够显著抑制多种 TNBC 细胞的增殖和 MDA-MB-231 异种移植模型的生长，而没有明显的毒性。我们的研究通过双重靶向 HDAC 和 G4 为 TNBC 的治疗提供了一种新策略。
