School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen 518060, China.
International Cancer Center, Shenzhen University Health Science Center, Shenzhen 518060, China.
Nucleic Acids Res. 2019 Nov 18;47(20):10529-10542. doi: 10.1093/nar/gkz835.
Conventional chemotherapy remains the primary treatment option for triple-negative breast cancer (TNBC). However, the current chemotherapeutic drugs have limited effects on TNBC, and often lead to serious side effects as well as drug resistance. Thus, more effective therapeutic options are sorely needed. As c-MYC oncogene is highly expressed during TNBC pathogenesis, inhibiting c-MYC expression would be an alternative anti-TNBC strategy. In this study, we designed and synthesized a serial of quinoxaline analogs that target c-MYC promoter G-quadruplex (G4), which is believed to be a repressor of c-MYC transcription. Among them, a difluoro-substituted quinoxaline QN-1 was identified as the most promising G4-stabilizing ligand with high selectivity to c-MYC G4 over other G4s, which is distinguished from many other reported ligands. Intracellular studies indicated that QN-1 induced cell cycle arrest and apoptosis, repressed metastasis and inhibited TNBC cell growth, primarily due to the downregulation of c-MYC transcription by a G4-dependent mechanism. Notably, inhibition by QN-1 was significantly greater for c-MYC than other G4-driven genes. Cancer cells with c-MYC overexpression were more sensitive to QN-1, relative to normal cells. Furthermore, QN-1 effectively suppressed tumor growth in a TNBC mouse model. Accordingly, this work provides an alternative strategy for treating TNBC.
传统化疗仍然是三阴性乳腺癌（TNBC）的主要治疗选择。然而，目前的化疗药物对 TNBC 的疗效有限，而且往往会导致严重的副作用和耐药性。因此，迫切需要更有效的治疗选择。由于 c-MYC 癌基因在 TNBC 发病机制中高度表达，抑制 c-MYC 表达将是一种替代的抗 TNBC 策略。在这项研究中，我们设计并合成了一系列针对 c-MYC 启动子 G-四链体（G4）的喹喔啉类似物，据信 G4 是 c-MYC 转录的抑制剂。其中，一种二氟取代的喹喔啉 QN-1 被鉴定为最有前途的 G4 稳定配体，对 c-MYC G4 具有高选择性，优于其他 G4，这与许多其他报道的配体不同。细胞内研究表明，QN-1 诱导细胞周期停滞和细胞凋亡，抑制转移并抑制 TNBC 细胞生长，主要是由于通过 G4 依赖的机制下调 c-MYC 转录。值得注意的是，QN-1 对 c-MYC 的抑制作用明显大于其他 G4 驱动的基因。与正常细胞相比，c-MYC 过表达的癌细胞对 QN-1 更敏感。此外，QN-1 有效地抑制了 TNBC 小鼠模型中的肿瘤生长。因此，这项工作为治疗 TNBC 提供了一种替代策略。
