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首页> 外文期刊>Cell cycle >S-phase inhibition of cell cycle progression by a novel class of pyridopyrimidine tyrosine kinase inhibitors.
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S-phase inhibition of cell cycle progression by a novel class of pyridopyrimidine tyrosine kinase inhibitors.

机译：新型的嘧啶嘧啶酪氨酸激酶抑制剂对细胞周期进程的S期抑制。

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Increased activity of the src family of oncogenic tyrosine kinases is seen in many human tumors and pharmacologic inhibitors of these kinases are investigated as potential anti-tumor agents. A family of pyrido [2, 3-d] pyrimidine compounds (PD) has been characterized as selective inhibitors of Src kinases. We studied the effects of this class of compounds on cancer cell lines and found that they were highly specific inhibitors of cell cycle progression. These compounds inhibit cells either in the mitotic phase or in mid S-phase; these two activities are mutually exclusive: no compound exerts both activities. We undertook experiments to determine the mechanistic basis for these differences and found additional biochemical activities associated with the S-phase inhibitors. Treatment of cells with the S-phase blocker PD179483 causes abnormal and persistent hyperactivation of Cdk2 and Cdc2 due to Tyr-15 dephosphorylation. These effects were associated with hyperphosphorylation of the upstream regulatory kinase Myt1 and Wee1. They were not observed with the anti-mitotic compounds. Furthermore, the S-phase inhibitors PD179483 and PD166326, but not the anti-mitotic compounds, inhibit Wee1 in vitro at concentrations that cause S-phase block in vivo. These data identify a novel subset of pyridopyrimidine compounds which are inhibitors of src and Wee1 kinases and which inhibit tumor cell growth through cell cycle arrest in mid S-phase.
机译：在许多人类肿瘤中发现致癌酪氨酸激酶的src家族活性增强，并且研究了这些激酶的药理抑制剂作为潜在的抗肿瘤药物。吡啶基[2，3-d]嘧啶化合物（PD）家族已被表征为Src激酶的选择性抑制剂。我们研究了这类化合物对癌细胞系的影响，发现它们是细胞周期进程的高度特异性抑制剂。这些化合物在有丝分裂期或中S期抑制细胞。这两个活动是互斥的：没有化合物同时发挥这两个活动。我们进行了实验以确定这些差异的机理基础，并发现了与S期抑制剂相关的其他生化活性。由于Tyr-15的去磷酸化作用，用S期阻滞剂PD179483处理细胞会导致Cdk2和Cdc2异常和持续过度活化。这些影响与上游调节激酶Myt1和Wee1的过度磷酸化有关。用抗有丝分裂化合物未观察到它们。此外，S期抑制剂PD179483和PD166326，但不是抗有丝分裂化合物，则在体外以引起体内S期阻滞的浓度抑制Wee1。这些数据确定了嘧啶嘧啶化合物的新子集，它们是src和Wee1激酶的抑制剂，并通过在S期中期阻滞细胞周期抑制肿瘤细胞的生长。

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