Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney Street, Cambridge, Massachusetts 02142, USA.
J Med Chem. 2013 Jun 13;56(11):4320-42. doi: 10.1021/jm4000038. Epub 2013 May 23.
Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates β-catenin concentrations, resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of β-catenin-mediated transcription and inhibit tumorigenesis. Compound 1 is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and molecular modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (39, 40).
端锚聚合酶（TNKS）是一种多聚 ADP-核糖基化蛋白（PARP），其活性抑制细胞轴蛋白水平并升高β-连环蛋白浓度，导致癌基因表达增加。端锚聚合酶（TNKS1 和 2）的抑制可能会降低β-连环蛋白介导的转录水平并抑制肿瘤发生。化合物 1 是一种先前描述的具有中等效力的端锚聚合酶抑制剂，但具有较差的药代动力学性质。在此，我们描述了基于结构的设计和分子建模在新型有效和选择性端锚聚合酶抑制剂中的应用，这些抑制剂具有改善的药代动力学性质（39、40）。
