Division of Nephrology, Department of Internal Medicine, University of California, Davis, Davis, CA, USA.
Cancer Biol Ther. 2013 Mar;14(3):278-85. doi: 10.4161/cbt.23374. Epub 2013 Jan 8.
p21 is a member of the cyclin kinase inhibitor family of proteins and plays pivotal roles in cellular proliferation as well as in the regulation of apoptosis, and thus has diverse functions in diseases as varied as cancer and atherosclerosis. In light of its pleiotropic effects and potential clinical relevance, new methods of attenuation of p21 protein levels by selective inhibitors are therefore powerful tools to probe malignant, infectious and other diseases. Here we introduce a novel p21 attenuator, UC2288, which possesses consistent and relatively selective activity for p21. UC2288 was synthesized based on the chemical model of sorafenib, a multikinase inhibitor that also attenuates p21, but unlike sorafenib, UC2288 did not inhibit Raf kinases or alter p-ERK protein levels. UC2288 decreased p21 mRNA expression independently of p53, and attenuated p21 protein levels with minimal effect on p21 protein stability. In addition, UC2288 inhibits cell growth in the kidney cancer cell lines (GI50 = approximately 10 µM) as well as multiple other cancer cell lines. Thus, this novel p21 inhibitor will be indispensable for exploring the function of p21, and upon further study may be translatable to the clinic.
p21 是细胞周期蛋白激酶抑制剂家族的一员，在细胞增殖以及细胞凋亡的调控中发挥关键作用，因此在癌症和动脉粥样硬化等各种疾病中具有多种功能。鉴于其多效性作用和潜在的临床相关性，通过选择性抑制剂降低 p21 蛋白水平的新方法是研究恶性、感染和其他疾病的有力工具。在这里，我们介绍了一种新型的 p21 衰减剂 UC2288，它对 p21 具有一致且相对选择性的活性。UC2288 是基于多激酶抑制剂索拉非尼的化学模型合成的，索拉非尼也能衰减 p21，但与索拉非尼不同的是，UC2288 不抑制 Raf 激酶或改变 p-ERK 蛋白水平。UC2288 独立于 p53 降低 p21 mRNA 表达，并衰减 p21 蛋白水平，对 p21 蛋白稳定性的影响最小。此外，UC2288 抑制肾癌细胞系（GI50 = 约 10 µM）以及其他多种癌细胞系的细胞生长。因此，这种新型的 p21 抑制剂对于探索 p21 的功能将是不可或缺的，并且在进一步研究后可能会转化为临床应用。
