Horizon Discovery, Cambridge Research Park, Cambridge CB25 9TL, UK.
Bioorg Med Chem Lett. 2013 Aug 1;23(15):4283-91. doi: 10.1016/j.bmcl.2013.05.088. Epub 2013 Jun 6.
Compelling data supports the hypothesis that Pin1 inhibitors will be useful for the therapy of cancer: Pin1 deficient mice resist the induction of breast cancers normally evoked by expression of MMTV-driven Ras or Erb2 alleles. While Pin1 poses challenges for drug discovery, several groups have identified potent antagonists by structure based drug design, significant progress has been made designing peptidic inhibitors and a number of natural products have been found that blockade Pin1, notably epigallocatchechin gallate (EGCG), a major flavonoid in green tea. Here we critically discuss the modes of action and likely specificity of these compounds, concluding that a suitable chemical biology tool for probing the function of Pin1 has yet to be found. We conclude by outlining some open questions regarding the target validation of Pin1 and the prospects for identification of improved inhibitors in the future.
强有力的数据支持 Pin1 抑制剂将可用于癌症治疗这一假说：Pin1 缺失的小鼠抵抗由 MMTV 驱动的 Ras 或 Erb2 等位基因表达引起的乳腺癌的诱导。虽然 Pin1 给药物发现带来了挑战，但几个小组通过基于结构的药物设计已经鉴定出有效的拮抗剂，在设计肽类抑制剂方面取得了重大进展，并且发现了一些天然产物可以阻断 Pin1，特别是表没食子儿茶素没食子酸酯（EGCG），绿茶中的一种主要类黄酮。在这里，我们批判性地讨论了这些化合物的作用模式和可能的特异性，得出的结论是，尚未找到合适的化学生物学工具来探测 Pin1 的功能。我们最后概述了关于 Pin1 的靶标验证的一些开放性问题以及未来鉴定改进抑制剂的前景。
