Departments of Medicinal Chemistry, College of Pharmacy, Rogel Cancer center, University of Michigan, Ann Arbor, Michigan 48109, United States.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan 48109, United States.
J Med Chem. 2020 Sep 10;63(17):9838-9855. doi: 10.1021/acs.jmedchem.0c01016. Epub 2020 Aug 28.
Redox modulators have been developed as an attractive approach to treat cancer. Herein, we report the synthesis, identification, and biological evaluation of a quinazolinedione reactive oxygen species (ROS) inducer, QD394, with significant cytotoxicity in pancreatic cancer cells. QD394 shows a transcriptomic profile remarkably similar to napabucasin, a cancer stemness inhibitor. Both small molecules inhibit STAT3 phosphorylation, increase cellular ROS, and decrease the GSH/GSSG ratio. Moreover, QD394 causes an iron- and ROS-dependent, GPX4 mediated cell death, suggesting ferroptosis as a major mechanism. Importantly, QD394 decreases the expression of LRPPRC and PNPT1, two proteins involved in mitochondrial RNA catabolic processes and both negatively correlated with the overall survival of pancreatic cancer patients. Pharmacokinetics-guided lead optimization resulted in the derivative QD394-Me, which showed improved plasma stability and reduced toxicity in mice compared to QD394. Overall, QD394 and QD394-Me represent novel ROS-inducing drug-like compounds warranting further development for the treatment of pancreatic cancer.
氧化还原调节剂已被开发为一种有吸引力的治疗癌症的方法。在此，我们报告了一种喹唑啉二酮活性氧（ROS）诱导剂 QD394 的合成、鉴定和生物学评价，它在胰腺癌细胞中具有显著的细胞毒性。QD394 表现出与 napabucasin（一种癌症干性抑制剂）非常相似的转录组特征。这两种小分子都抑制 STAT3 磷酸化，增加细胞内 ROS，并降低 GSH/GSSG 比值。此外，QD394 导致铁和 ROS 依赖性、GPX4 介导的细胞死亡，表明铁死亡是一种主要机制。重要的是，QD394 降低了两个参与线粒体 RNA 代谢过程的蛋白质 LRPPRC 和 PNPT1 的表达，这两种蛋白质与胰腺癌患者的总生存期呈负相关。基于药代动力学的先导化合物优化得到了衍生物 QD394-Me，与 QD394 相比，它在小鼠体内具有更好的血浆稳定性和更低的毒性。总的来说，QD394 和 QD394-Me 代表了新型的 ROS 诱导药物样化合物，值得进一步开发用于治疗胰腺癌。
