Repurposing of the CDK inhibitor PHA-767491 as a NRF2 inhibitor drug candidate for cancer therapy via redox modulation.
Repurposing of the CDK inhibitor PHA-767491 as a NRF2 inhibitor drug candidate for cancer therapy via redox modulation.
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DOI：
10.1007/s10637-017-0557-6
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发表时间：
2018-08
影响因子：
3.4
通讯作者：
Zakrzewski, Johannes L.
中科院分区：
文献类型：
--
作者：
Liu, Hsiu-Yu;Tuckett, Andrea Z.;Fennell, Myles;Garippa, Ralph;Zakrzewski, Johannes L.
关键词：
氧化应激和细胞反应机制，如NRF2介导的抗氧化反应，在健康和疾病细胞中发挥着不同的作用。不断地产生和消除高水平的活性氧物种是许多癌细胞类型的标志；在健康细胞的稳定状态下不会观察到这种现象。因此，对NRF2转录活性和细胞氧化还原动态平衡的操纵有可能通过优先靶向癌细胞诱导氧化应激而用于癌症治疗。我们发现，NRF2抑制剂Brusatol引发了氧化应激增加，同时损害了多发性骨髓瘤细胞的生存和增殖。采用重新定位的方法，我们发现CDC7/CDK9抑制剂PHA-767491也是NRF2转录活性的有效抑制剂。该分子是通过对约5900个类药物分子的文库进行高通量筛选而确定的。筛选方法包括两种基于细胞的检测方法：a)NRF2细胞核易位检测，b)NRF2荧光素酶报告基因检测。在多发性骨髓瘤细胞中进行验证分析，包括检测线粒体超氧化物歧化水平和MTS分析。我们发现PHA-767491对多发性骨髓瘤细胞的作用与抑制核转位、增加线粒体超氧化物歧化水平和抑制细胞生长有关。我们的研究结果表明，PHA-767491是一种很有前途的癌症治疗药物，其抑制NRF2的效力有助于其抗癌特性。
Oxidative stress and cellular response mechanisms such as NRF2-mediated antioxidant responses play differential roles in healthy and diseased cells. Constant generation and elimination of high levels of reactive oxygen species is a hallmark of many cancer cell types; this phenomenon is not observed during steady state of healthy cells. Manipulation of NRF2 transcriptional activity and the cellular redox homeostasis therefore has potential to be therapeutically exploitable for cancer therapy by preferentially targeting cancer cells for induction of oxidative stress. We found that the NRF2 inhibitor brusatol triggered increased oxidative stress while compromising viability and proliferation of multiple myeloma cells. Using a repurposing approach we discovered that the Cdc7/CDK9 inhibitor PHA-767491 is also a potent inhibitor of NRF2 transcriptional activity. The molecule was identified by high throughput screening of a library of about 5,900 drug-like molecules. Screening assays included two cell-based assays using HepG2 hepatocellular carcinoma cells: a) A NRF2 nuclear translocation assay, and b) A NRF2 luciferase reporter assay. Validation assays were performed in multiple myeloma cells and included detection of mitochondrial superoxide levels and MTS assays. We found that PHA-767491 treatment of multiple myeloma cells was associated with inhibition of nuclear translocation of NRF2, increased mitochondrial superoxide levels and inhibition of cell growth. Our findings suggest that PHA-767491 is a promising drug candidate for cancer therapy with NRF2 inhibitory potency contributing to its anti-cancer properties.
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