Cell cycle and biochemical effects of PD 0183812 - a potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6
Cell cycle and biochemical effects of PD 0183812 - a potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6
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DOI：
10.1074/jbc.m008867200
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发表时间：
2001-05-18
影响因子：
4.8
通讯作者：
Garrett, MD
中科院分区：
文献类型：
--
作者：
Fry, DW;Bedford, DC;Garrett, MD
通过细胞周期的G（1）期的进展需要通过细胞周期蛋白D依赖性激酶CDK 4和CDK 6磷酸化视网膜母细胞瘤基因产物（pRb），其活性可被CDK抑制剂p16（INK 4A）特异性阻断。pRb/细胞周期蛋白D/p16（INK 4A）通路的失调是人类癌症中最常见的事件之一，并且已经导致这样的建议，即细胞周期蛋白D依赖性激酶活性的抑制可能具有作为抗癌治疗的治疗价值。通过对化学文库的筛选，我们初步鉴定了[2，3-d]吡啶并嘧啶类化合物为CDK 4的抑制剂。CDK 4和CDK 6激酶活性的选择性抑制剂，其与ATP竞争。流式细胞术实验显示，在所测试的细胞系中，当用PD 0183812处理时，仅表达pRb的那些细胞系表现出G（1）停滞。这种停滞在孵育时间和效力方面与pRb磷酸化的丧失和增殖的阻断相关，这是可逆的，这些结果表明，这种化学类别的化合物作为治疗剂在治疗具有功能性pRb的肿瘤中的潜在用途，所述功能性pRb在pRb/细胞周期蛋白D/p16（INK 4A）途径的其他成员中具有细胞周期畸变。
Progression through the G(1) phase of the cell cycle requires phosphorylation of the retinoblastoma gene product (pRb) by the cyclin D-dependent kinases CDK4 and CDK6, whose activity can specifically be blocked by the CDK inhibitor p16(INK4A). Misregulation of the pRb/cyclin D/p16(INK4A) pathway is one of the most common events in human cancer and has lead to the suggestion that inhibition of cyclin D-dependent kinase activity may have therapeutic value as an anticancer treatment. Through screening of a chemical library, we initially identified the [2,3-d]pyridopyrimidines as inhibitors of CDK4, Chemical modification resulted in the identification of PD 0183812 as a potent and highly se!lective inhibitor of both CDK4 and CDK6 kinase activity, which is competitive with ATP, Flow cytometry experiments showed that of the cell lines tested, only those expressing pRb demonstrated a G(1) arrest when treated with PD 0183812, This arrest correlated in terms of incubation time and potency with a loss of pRb phosphorylation and a block in proliferation, which was reversible, These results suggest a potential use of this chemical class of compounds as therapeutic agents in the treatment of tumors with functional pRb, possessing cell cycle aberrations in other members of the pRb/cyclin D/p16(INK4A) pathway.