靶向 Wip1 瓣状结构域抑制剂类别的活性的化学特征。
Chemical Features Important for Activity in a Class of Inhibitors Targeting the Wip1 Flap Subdomain.
机构信息
Laboratory of Cell Biology, National Cancer Institute, US National Institutes of Health, Bethesda, MD, 20892, USA.
Synthetic Bioactive Molecules Section, LBC, NIDDK, US National Institutes of Health, 8 Center Drive, Room 404, Bethesda, MD, 20892, USA.
出版信息
ChemMedChem. 2018 May 8;13(9):894-901. doi: 10.1002/cmdc.201700779. Epub 2018 Apr 6.
The wild-type p53 induced phosphatase 1, Wip1 (PP2Cδ), is a protein phosphatase 2C (PP2C) family serine/threonine phosphatase that negatively regulates the function of the tumor suppressor p53 and several of its positive regulators such as ATM, Chk1, Chk2, Mdm2, and p38 MAPK. Wip1 dephosphorylates and inactivates its protein targets, which are critical for cellular stress responses. Additionally, Wip1 is frequently amplified and overexpressed in several human cancer types. Because of its negative role in regulating the function of tumor suppressor proteins, Wip1 has been identified as a potential therapeutic target in various types of cancers. Based on a recently reported Wip1 inhibitor (G-1), we performed an extensive structure-activity relationship (SAR) analysis. This led us to interesting findings in SAR trends and to the discovery of new chemical analogues with good specificity and bioavailability.
野生型 p53 诱导磷酸酶 1（Wip1，即 PP2Cδ）是蛋白磷酸酶 2C（PP2C）家族丝氨酸/苏氨酸磷酸酶，可负调控肿瘤抑制因子 p53 及其多个正向调控因子（如 ATM、Chk1、Chk2、Mdm2 和 p38 MAPK）的功能。Wip1 可使蛋白靶标去磷酸化而失活，这些靶标对于细胞应激反应至关重要。此外，Wip1 在多种人类癌症类型中经常扩增和过表达。由于其在调节肿瘤抑制蛋白功能方面的负面作用，Wip1 已被确定为各种类型癌症的潜在治疗靶点。基于最近报道的 Wip1 抑制剂（G-1），我们进行了广泛的结构-活性关系（SAR）分析。这使我们在 SAR 趋势方面有了有趣的发现，并发现了具有良好特异性和生物利用度的新型化学类似物。
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