Chao S H, Fujinaga K, Marion J E, Taube R, Sausville E A, Senderowicz A M, Peterlin B M, Price D H
Molecular Biology Program and the Department of Biochemistry, University of Iowa, Iowa City, Iowa 52242, USA.
J Biol Chem. 2000 Sep 15;275(37):28345-8. doi: 10.1074/jbc.C000446200.
Flavopiridol (L86-8275, HMR1275) is a cyclin-dependent kinase (Cdk) inhibitor that is in clinical trials as a cancer treatment because of its antiproliferative properties. We found that the flavonoid potently inhibited transcription by RNA polymerase II in vitro by blocking the transition into productive elongation, a step controlled by P-TEFb. The ability of P-TEFb to phosphorylate the carboxyl-terminal domain of the large subunit of RNA polymerase II was inhibited by flavopiridol with a K(i) of 3 nm. Interestingly, the drug was not competitive with ATP. P-TEFb composed of Cdk9 and cyclin T1 is a required cellular cofactor for the human immunodeficiency virus (HIV-1) transactivator, Tat. Consistent with its ability to inhibit P-TEFb, flavopiridol blocked Tat transactivation of the viral promoter in vitro. Furthermore, flavopiridol blocked HIV-1 replication in both single-round and viral spread assays with an IC(50) of less than 10 nm.
黄酮哌啶醇（L86 - 8275，HMR1275）是一种细胞周期蛋白依赖性激酶（Cdk）抑制剂，因其具有抗增殖特性，正在作为癌症治疗药物进行临床试验。我们发现，这种黄酮类化合物在体外通过阻断向有效延伸的转变，有力地抑制了RNA聚合酶II的转录，这一步骤由P - TEFb控制。黄酮哌啶醇抑制P - TEFb使RNA聚合酶II大亚基的羧基末端结构域磷酸化的能力，其抑制常数（K(i)）为3纳米。有趣的是，该药物与ATP不存在竞争性。由Cdk9和细胞周期蛋白T1组成的P - TEFb是人类免疫缺陷病毒（HIV - 1）反式激活因子Tat所需的细胞辅因子。与其抑制P - TEFb的能力一致，黄酮哌啶醇在体外阻断了病毒启动子的Tat反式激活。此外，在单轮和病毒传播试验中，黄酮哌啶醇均能阻断HIV - 1复制，其半数抑制浓度（IC(50)）小于10纳米。
