Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO, 80045, USA.
ChemMedChem. 2018 Aug 20;13(16):1681-1694. doi: 10.1002/cmdc.201800188. Epub 2018 Jul 11.
WEE1 kinase regulates the G /M cell-cycle checkpoint, a critical mechanism for DNA repair in cancer cells that can confer resistance to DNA-damaging agents. We previously reported a series of pyrazolopyrimidinones based on AZD1775, a known WEE1 inhibitor, as an initial investigation into the structural requirements for WEE1 inhibition. Our lead inhibitor demonstrated WEE1 inhibition in the same nanomolar range as AZD1775, and potentiated the effects of cisplatin in medulloblastoma cells, but had reduced single-agent cytotoxicity. These results prompted the development of a more comprehensive series of WEE1 inhibitors. Herein we report a series of pyrazolopyrimidinones and identify a more potent WEE1 inhibitor than AZD1775 and additional compounds that demonstrate that WEE1 inhibition can be achieved with reduced single-agent cytotoxicity. These studies support that WEE1 inhibition can be uncoupled from the potent cytotoxic effects observed with AZD1775, and this may have important ramifications in the clinical setting where WEE1 inhibitors are used as chemosensitizers for DNA-targeted chemotherapy.
WEE1 激酶调节 G2/M 细胞周期检查点，这是癌细胞中 DNA 修复的关键机制，可赋予其对 DNA 损伤剂的抗性。我们之前报道了一系列基于 AZD1775 的吡唑并嘧啶酮，AZD1775 是一种已知的 WEE1 抑制剂，作为对 WEE1 抑制结构要求的初步研究。我们的先导抑制剂在与 AZD1775 相同的纳摩尔范围内抑制 WEE1，并增强了顺铂在成神经管细胞瘤细胞中的作用，但单药细胞毒性降低。这些结果促使我们开发了更全面的 WEE1 抑制剂系列。在此，我们报告了一系列吡唑并嘧啶酮，并确定了一种比 AZD1775 更有效的 WEE1 抑制剂，以及其他一些化合物，这些化合物表明 WEE1 抑制可以在降低单药细胞毒性的情况下实现。这些研究表明，WEE1 抑制可以与 AZD1775 观察到的强烈细胞毒性作用脱钩，这在临床环境中具有重要意义，在该环境中，WEE1 抑制剂被用作 DNA 靶向化疗的化学增敏剂。
