Turkson James, Kim Joon S, Zhang Shumin, Yuan Jing, Huang Mei, Glenn Matthew, Haura Eric, Sebti Said, Hamilton Andrew D, Jove Richard
Molecular Oncology and Drug Discovery Programs, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Mol Cancer Ther. 2004 Mar;3(3):261-9.
The critical role of signal transducer and activator of transcription 3 (Stat3) in the growth and survival of human tumor cells identifies it as a promising target for cancer drug discovery. We previously identified a Stat3 SH2 domain-binding phosphopeptide, PYLKTK, and its tripeptide derivatives, PYL and AYL (where Y represents phosphotyrosine), which inhibit Stat3 biochemical activity and biological function. Here, we report novel peptidomimetic compounds based on PYL (or AYL) with substitution of the Y-1 residue by benzyl, pyridyl, or pyrazinyl derivatives that are selective and greater than 5-fold more potent in disrupting Stat3 activity in vitro than lead tripeptides. The biological activities of these derivatives mirror that originally observed for peptides. In this context, the representative peptidomimetic ISS 610 with 4-cyanobenzoate substitution inhibits constitutive Stat3 activity in Src-transformed mouse fibroblasts and human breast and lung carcinoma cells. This effect is not evident with the non-phosphorylated counterpart, ISS 610NP, consistent with interaction of peptidomimetics with the SH2 domain of Stat3. Moreover, ISS 610 induces cell growth inhibition and apoptosis of Src-transformed fibroblasts that contain persistently active Stat3. We present the first report of a peptidomimetic approach to design of small-molecule inhibitors of Stat3 that are also among the first examples of disruptors of transcription factor dimerization with the potential for novel cancer therapy.
信号转导子和转录激活子3（Stat3）在人类肿瘤细胞的生长和存活中起着关键作用，这使其成为癌症药物研发的一个有前景的靶点。我们之前鉴定出一种Stat3 SH2结构域结合磷酸肽PYLKTK及其三肽衍生物PYL和AYL（其中Y代表磷酸化酪氨酸），它们能抑制Stat3的生化活性和生物学功能。在此，我们报告了基于PYL（或AYL）的新型拟肽化合物，其Y-1残基被苄基、吡啶基或吡嗪基衍生物取代，这些化合物具有选择性，在体外破坏Stat3活性方面比先导三肽强5倍以上。这些衍生物的生物学活性与最初在肽中观察到的一致。在这种情况下，具有4-氰基苯甲酸酯取代的代表性拟肽ISS 610可抑制Src转化的小鼠成纤维细胞以及人乳腺癌和肺癌细胞中的组成型Stat3活性。非磷酸化对应物ISS 610NP则没有这种明显效果，这与拟肽与Stat3的SH2结构域相互作用一致。此外，ISS 610可诱导含有持续激活的Stat3的Src转化成纤维细胞的细胞生长抑制和凋亡。我们首次报道了一种基于拟肽方法设计Stat3小分子抑制剂，这也是转录因子二聚化破坏剂的首批实例之一，具有新型癌症治疗的潜力。
