Signal transducers and activators of transcription 5 (STAT5s) are crucial effectors of tyrosine kinase oncogenes in myeloid leukemias. Inhibition of STAT5 would contribute to reducing the survival of leukemic cells and also tackling their chemoresistance. In a first screening experiment, we identified hit 13 as able to inhibit STAT5 phosphorylation and leukemic cell growth. The synthesis of 18 analogues of 13 allowed us to identify one compound, 17f, as having the most potent antileukemic effect. 17f inhibited the growth of acute and chronic myeloid leukemia cells and the phosphorylation and transcriptional activity of STAT5. Importantly, 17f had minimal effects on bone marrow stromal cells that play vital functions in the microenvironment of hematopoietic and leukemic cells. We also demonstrated that 17f inhibits STAT5 but not STAT3, AKT, or Erk1/2 phosphorylation. These results suggest that 17f might be a new lead molecule targeting STAT5 signaling in myeloid leukemias.

中文翻译：

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髓样白血病中的新型抑制剂靶向信号转导子和转录5（STAT5）信号激活剂。

信号转导子和转录激活因子5（STAT5s）是髓样白血病中酪氨酸激酶致癌基因的关键效应子。抑制STAT5将有助于降低白血病细胞的存活率，并且还可以增强其化学抗性。在第一个筛选实验中，我们确定命中13位能够抑制STAT5磷酸化和白血病细胞生长。的18个类似物的合成13使我们能够确定一种化合物，17F，作为具有最有效的抗白血病作用。17f抑制急慢性髓性白血病细胞的生长以及STAT5的磷酸化和转录活性。重要的是17楼对在造血细胞和白血病细胞的微环境中起重要作用的骨髓基质细胞的作用微乎其微。我们还证明了17f抑制STAT5，但不抑制STAT3，AKT或Erk1 / 2磷酸化。这些结果表明17f可能是针对髓样白血病中STAT5信号转导的新的先导分子。