Department of Medicinal Chemistry, College of Pharmacy, University of Michigan , 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States.
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California , 1985 Zonal Avenue, Los Angeles, California 90033, United States.
J Med Chem. 2018 Feb 22;61(4):1576-1594. doi: 10.1021/acs.jmedchem.7b01463. Epub 2018 Feb 2.
Altering redox homeostasis provides distinctive therapeutic opportunities for the treatment of pancreatic cancer. Quinazolinediones (QDs) are novel redox modulators that we previously showed to induce potent growth inhibition in pancreatic ductal adenocarcinoma (PDAC) cell lines. Our lead optimization campaign yielded QD325 as the most potent redox modulator candidate inducing substantial reactive oxygen species (ROS) in PDAC cells. Nascent RNA sequencing following treatments with the QD compounds revealed induction of stress responses in nucleus, endoplasmic reticulum, and mitochondria of pancreatic cancer cells. Furthermore, the QD compounds induced Nrf2-mediated oxidative stress and unfolded protein responses as demonstrated by dose-dependent increases in RNA synthesis of representative genes such as NQO1, HMOX1, DDIT3, and HSPA5. At higher concentrations, the QDs blocked mitochondrial function by inhibiting mtDNA transcription and downregulating the mtDNA-encoded OXPHOS enzymes. Importantly, treatments with QD325 were well tolerated in vivo and significantly delayed tumor growth in mice. Our study supports the development of QD325 as a new therapeutic in the treatment of PDAC.
改变氧化还原稳态为治疗胰腺癌提供了独特的治疗机会。喹唑啉二酮（QDs）是一种新型的氧化还原调节剂，我们之前的研究表明，它能在胰腺导管腺癌（PDAC）细胞系中诱导强烈的生长抑制作用。我们的先导化合物优化研究得到了 QD325，它是最有效的氧化还原调节剂候选物，能在 PDAC 细胞中诱导大量的活性氧（ROS）。用 QD 化合物处理后进行的新生 RNA 测序显示，这些化合物能诱导胰腺癌细胞的核、内质网和线粒体中的应激反应。此外，QD 化合物通过诱导 Nrf2 介导的氧化应激和未折叠蛋白反应，如代表性基因如 NQO1、HMOX1、DDIT3 和 HSPA5 的 RNA 合成剂量依赖性增加来证明这一点。在较高浓度下，QD 会通过抑制 mtDNA 转录和下调 mtDNA 编码的 OXPHOS 酶来阻断线粒体功能。重要的是，QD325 在体内的治疗耐受性良好，并能显著延缓小鼠肿瘤的生长。我们的研究支持将 QD325 开发为治疗 PDAC 的一种新疗法。
