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.

中文翻译：

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对一类针对 Wip1 Flap 子域的抑制剂的活性很重要的化学特征

野生型 p53 诱导的磷酸酶 1 Wip1 (PP2Cδ) 是一种蛋白磷酸酶 2C (PP2C) 家族丝氨酸/苏氨酸磷酸酶，可负调节肿瘤抑制因子 p53 及其几个正调节因子（如 ATM、Chk1、Chk2）的功能、Mdm2 和 p38 MAPK。Wip1 使其蛋白质靶标去磷酸化并使其失活，这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被扩增和过度表达。由于其在调节肿瘤抑制蛋白功能中的负面作用，Wip1已被确定为多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 )，我们进行了广泛的构效关系 (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化学类似物。