CDK9 inhibitor 是一种新型的选择性 CDK9 抑制剂，用于治疗 HIV 感染，对 CDK9/CycT1 的 IC50 为 39 nM，从参考化合物 87 中提取。
CDK9 inhibitor is a small-molecule selective inhibitor of CDK9 (cyclin dependent kinase 9) with IC50 value of 39 nM [1].
CDKs are a group of serine/threonine kinases and are widely spread in all known eukaryotes. CDKs are activated through binding to cyclins and forming heterodimers. In the dimer, CDK acts as a catalytic subunit and phosphorylates the down-stream proteins such as nuclear lamina protein, nucleolin and histone H1. Through this way, CDKs take participate in the cell cycle regulation. CDK9 is a special member of the CDK family. It can affect the elongation phase of transcription through phosphorylating RNA polymerase II. The partner of it is positive elongation factor b (P-TEFb). It is reported that CDK9 is necessary for the infection of many kinds of viruses such as HIV-1 and HSV1 [1].
CDK9 inhibitor is a 4-aminophenyl derivative based on the (6-phenyl-pyrimidin-4-yl)-phenylamine structure. It showed elevated selectivity against CDK9 than the previous found inhibitors. The IC50 values of CDK9 inhibitor for CDK1/CycB, CDK2/CycE, CDK3/CycE, CDK4/CycD1, CDK5/p35, CDK6/CycD1 and CDK7/CycH are all higher than 1 μM. CDK9 inhibitor has no cytotoxicity. The treatment of CDK9 inhibitor at concentrations of 1 μM and 2 μM resulted in the cell viabilities of 101% and 115%, respectively. It also showed no significant toxicity in H9 cells. In the p24 assay, CDK9 inhibitor exerted its potency in inhibiting HIV-1 propagation with about 10% reduction of p24 production [1].
参考文献:
1.Németh G, Varga Z, Greff Z, et al. Novel, selective CDK9 inhibitors for the treatment of HIV infection. Curr Med Chem, 2011;18(3):342-58.
| Cell experiment [1]: | |
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Cell lines |
MT4 cells |
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Preparation method |
This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
2.5 μM; 1 week |
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Applications |
In HIV-1 infected MT4 cells, CDK9 Inhibitor at 2.5 μM potently inhibited HIV-1 propagation due to positive elongation factor b (P-TEFb) inhibition. Moreover, in MT4 cells, CDK9 Inhibitor at the concentrations of 1 μM and 2 μM resulted in the cell viabilities of 101% and 115%, respectively, which implied CDK9 Inhibitor had no cytotoxicity. In the p24 assay, CDK9 Inhibitor down-regulated the expression of p24 protein by 10%. |
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参考文献: [1]. Németh G, Varga Z, Greff Z, et al. Novel, selective CDK9 inhibitors for the treatment of HIV infection. Curr Med Chem, 2011;18(3):342-58. | |
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