Pecháčková Soňa, Burdová Kamila, Macurek Libor
Department of Cancer Cell Biology, Institute of Molecular Genetics of the ASCR, CZ-14220, Prague, Czech Republic.
J Mol Med (Berl). 2017 Jun;95(6):589-599. doi: 10.1007/s00109-017-1536-2. Epub 2017 Apr 24.
DNA damage response (DDR) pathway protects cells from genome instability and prevents cancer development. Tumor suppressor p53 is a key molecule that interconnects DDR, cell cycle checkpoints, and cell fate decisions in the presence of genotoxic stress. Inactivating mutations in TP53 and other genes implicated in DDR potentiate cancer development and also influence the sensitivity of cancer cells to treatment. Protein phosphatase 2C delta (referred to as WIP1) is a negative regulator of DDR and has been proposed as potential pharmaceutical target. Until recently, exploitation of WIP1 inhibition for suppression of cancer cell growth was compromised by the lack of selective small-molecule inhibitors effective at cellular and organismal levels. Here, we review recent advances in development of WIP1 inhibitors and discuss their potential use in cancer treatment.
DNA损伤反应（DDR）通路可保护细胞免受基因组不稳定的影响，并预防癌症的发生。肿瘤抑制因子p53是一个关键分子，在存在基因毒性应激的情况下，它将DNA损伤反应、细胞周期检查点和细胞命运决定联系起来。TP53及其他与DNA损伤反应相关基因的失活突变会促进癌症的发生，同时也会影响癌细胞对治疗的敏感性。蛋白磷酸酶2Cδ（简称为WIP1）是DNA损伤反应的负调节因子，已被提议作为潜在的药物靶点。直到最近，由于缺乏在细胞和生物体水平有效的选择性小分子抑制剂，利用WIP1抑制来抑制癌细胞生长的研究受到了阻碍。在此，我们综述了WIP1抑制剂开发的最新进展，并讨论了它们在癌症治疗中的潜在用途。
