A WEE1 Inhibitor Analog of AZD1775 Maintains Synergy with Cisplatin and Demonstrates Reduced Single-Agent Cytotoxicity in Medulloblastoma Cells
A WEE1 Inhibitor Analog of AZD1775 Maintains Synergy with Cisplatin and Demonstrates Reduced Single-Agent Cytotoxicity in Medulloblastoma Cells
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DOI：
10.1021/acschembio.5b00725
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发表时间：
2016-04-01
影响因子：
4
通讯作者：
Reigan, Philip
中科院分区：
文献类型：
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作者：
Matheson, Christopher J.;Venkataraman, Sujatha;Reigan, Philip
目前髓母细胞瘤的治疗方法包括手术切除、放射治疗和细胞毒化疗。虽然这种方法提高了存活率，但临床疗效所需的大剂量化疗往往会导致持久的神经认知缺陷和其他不良事件。因此，开发化疗增敏剂，减少细胞毒药物的剂量，限制其不良反应，同时保持其临床疗效，将是治疗髓母细胞瘤的一种有吸引力的方法。我们之前通过对基因表达的综合基因组分析和对髓母细胞瘤细胞和组织的全基因组siRNA筛选，确定WEE1激酶是髓母细胞瘤的新的分子靶点。此外，我们还证明了WEE1可以预防顺铂引起的DNA损伤诱导的细胞死亡，并且WEE1抑制剂AZD1775与顺铂显示出协同作用。AZD1775是作为一种WEE1抑制剂而开发的，最初是从高通量屏幕上获得的。然而，由于缺乏AZD1775的结构活性数据，我们开发了一小系列类似物来确定WEE1抑制的要求，并进一步研究WEE1抑制在髓母细胞瘤中的作用。有趣的是，在与AZD1775相同的纳摩尔范围内抑制WEE1的化合物与AZD1775相比显著降低了单药细胞毒性，并在髓母细胞瘤细胞中显示出与顺铂的协同活性。AZD1775的强大细胞毒性与WEE1抑制无关，可能导致剂量限制性毒性并加剧不良反应；因此，可以在较高浓度下使用细胞毒性较低的WEE1抑制剂来增强肿瘤的化疗敏感性，并增强顺铂等DNA损伤剂的效果。
The current treatment for medulloblastoma includes surgical resection, radiation, and cytotoxic chemotherapy. Although this approach has improved survival rates, the high doses of chemotherapy required for clinical efficacy often result in lasting neurocognitive defects and other adverse events. Therefore, the development of chemosensitizing agents that allow dose reductions of cytotoxic agents, limiting their adverse effects but maintaining their clinical efficacy, would be an attractive approach to treat medulloblastoma. We previously identified WEE1 kinase as a new molecular target for medulloblastoma from an integrated genomic analysis of gene expression and a kinome-wide siRNA screen of medulloblastoma cells and tissue. In addition, we demonstrated that WEE1 prevents DNA damage-induced cell death by cisplatin and that the WEE1 inhibitor AZD1775 displays synergistic activity with cisplatin. AZD1775 was developed as a WEE1 inhibitor from an initial hit from a high throughput screen. However, given the lack of structure activity data for AZD1775, we developed a small series of analogs to determine the requirements for WEE1 inhibition and further examine the effects of WEE1 inhibition in medulloblastoma. Interestingly, the compounds that inhibited WEE1 in the same nanomolar range as AZD1775 had significantly reduced single agent cytotoxicity compared with AZD1775 and displayed synergistic activity with cisplatin in medulloblastoma cells. The potent cytotoxicity of AZD1775, unrelated to WEE1 inhibition, may result in dose-limiting toxicities and exacerbate adverse effects; therefore, WEE1 inhibitors that demonstrate low cytotoxicity could be dosed at higher concentrations to chemosensitize the tumor and potentiate the effect of DNA-damaging agents such as cisplatin.