Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, United States.
Department of Medicinal Chemistry, College of Pharmacy, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, United States; Key Laboratory of Medicinal Chemistry for Natural Resource, School of Chemical Science and Technology, Yunnan University, Kunming, 650091, China.
Eur J Med Chem. 2018 Oct 5;158:884-895. doi: 10.1016/j.ejmech.2018.09.037. Epub 2018 Sep 15.
Inhibition of proteasome activity blocks the degradation of dysfunctional proteins and induces cancer cell death due to cellular stress. Thus, proteasome inhibitors represent an attractive class of anticancer agents, and bortezomib, carfilzomib and ixazomib have been FDA-approved to treat multiple myeloma. However, cancer cells acquire resistance to these inhibitors through point mutations in the proteasome catalytic subunit or induction of alternative compensatory mechanisms. In this study, we identified a quinolin-chlorobenzothioate, QCBT7, as a new proteasome inhibitor showing cytotoxicity in a panel of cancer cell lines. QCBT7 is a more stable derivative of quinoline-8-thiol that targets the regulatory subunit instead of the catalytic subunit of the proteasome. QCBT7 caused the accumulation of ubiquitylated proteins in the cancer cells, indicating its proteasome inhibitory activity. Additionally, QCBT7 increased the expression of a set of genes (PFKFB4, CHOP, HMOX1 and SLC7A11) at both nascent RNA and protein levels, similarly to the known proteasome inhibitors MG132 and ixazomib. Together, QCBT7 induces proteasome inhibition, hypoxic response, endoplasmic reticulum stress and glycolysis, finally leading to cell death. Importantly, we have identified PFKFB4 as a potential biomarker of proteasome inhibitors that can be used to monitor treatment response.
蛋白酶体活性的抑制会阻止功能失调蛋白的降解，并导致细胞应激引起的癌细胞死亡。因此，蛋白酶体抑制剂是一类有吸引力的抗癌药物，硼替佐米、卡非佐米和伊沙佐米已被 FDA 批准用于治疗多发性骨髓瘤。然而，癌细胞通过蛋白酶体催化亚基的点突变或诱导替代补偿机制获得对这些抑制剂的耐药性。在这项研究中，我们鉴定了一种喹啉-氯苯并噻吩，QCBT7，作为一种新的蛋白酶体抑制剂，在一系列癌细胞系中显示出细胞毒性。QCBT7 是喹啉-8-硫醇的更稳定衍生物，它靶向蛋白酶体的调节亚基而不是催化亚基。QCBT7 导致癌细胞中泛素化蛋白的积累，表明其具有蛋白酶体抑制活性。此外，QCBT7 增加了一组基因（PFKFB4、CHOP、HMOX1 和 SLC7A11）在新生 RNA 和蛋白质水平的表达，与已知的蛋白酶体抑制剂 MG132 和伊沙佐米相似。总之，QCBT7 诱导蛋白酶体抑制、低氧反应、内质网应激和糖酵解，最终导致细胞死亡。重要的是，我们已经确定 PFKFB4 是蛋白酶体抑制剂的潜在生物标志物，可用于监测治疗反应。
