Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, V20-2102, Aurora, CO 80045, USA.
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, V20-2102, Aurora, CO 80045, USA.
Trends Pharmacol Sci. 2016 Oct;37(10):872-881. doi: 10.1016/j.tips.2016.06.006. Epub 2016 Jul 14.
WEE1 kinase plays a crucial role in the G2-M cell-cycle checkpoint arrest for DNA repair before mitotic entry. Normal cells repair damaged DNA during G1 arrest; however, cancer cells often have a deficient G1-S checkpoint and depend on a functional G2-M checkpoint for DNA repair. WEE1 is expressed at high levels in various cancer types including breast cancers, leukemia, melanoma, and adult and pediatric brain tumors. Many of these cancers are treated with DNA-damaging agents; therefore, targeting WEE1 for inhibition and compromising the G2-M checkpoint presents an opportunity to potentiate therapy. In this review we summarize the current WEE1 inhibitors, the potential for further inhibitor development, and the challenges in the clinic for the WEE1 inhibitor strategy.
WEE1 激酶在有丝分裂前的 G2-M 细胞周期检查点阻滞中对于 DNA 修复起着至关重要的作用。正常细胞在 G1 期阻滞时修复受损的 DNA；然而，癌细胞通常存在缺陷的 G1-S 检查点，并且依赖于功能正常的 G2-M 检查点来进行 DNA 修复。WEE1 在包括乳腺癌、白血病、黑色素瘤以及成人和儿科脑肿瘤在内的多种癌症类型中高表达。这些癌症中的许多都用 DNA 损伤剂进行治疗；因此，针对 WEE1 进行抑制并破坏 G2-M 检查点为增强治疗提供了机会。在这篇综述中，我们总结了当前的 WEE1 抑制剂、进一步开发抑制剂的潜力以及 WEE1 抑制剂策略在临床中的挑战。
