生物活性 | |||
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描述 | The CDKs (cyclin dependent kinases), as direct regulators of specific phases of the cell cycle, can control cellular proliferation and transcription with their activating cyclin partners and subunit inhibitors. Thus, the inhibition of CDKs can be assessed with monitoring the phosphorylation state of specific substrates. For example, decreased phosphorylation of the CDK1 substrate PP1 (T320) and the CDK2 substrates Rb (T821) and NPM (T199) can indicated the inhibition of the CDKs. Decreased phosphorylation of pSer5 and pSer2 of RNA pol II CTD would indicate inhibition of CDKs 7 and 9, respectively. AT7519 Hydrochloride is the hydrochloride form of AT7519. AT7519 is a pan-CDKs inhibitor with IC50 values of 47, 13, <10nM for CDK2/CyclinA, CDK5/p35 and CDK9/CyclinT, and modest activity against CDK1/CyclinB, CDK3/CyclinE, CDK4/CyclinD1 and CDK6/CyclinD3 with IC50 values of 210, 360, 100 and 170nM, respectively (measured by in vitro kinase assays) . Treatment with 0.05-1uM AT7519 for 24 h was sufficient to inhibit phosphorylation of the CDK1 substrate PP1 (T320) and the CDK2 substrates Rb (T821) and NPM (T199) in HCT116 cells. AT7519 on concentration of 0.5uM induced rapid dephosphorylation at both RNA pol II CTD at both the serine 2 and serine 5 sites. AT7519 showed antiproliferative activity and apoptosis-induction in a panel of human tumor cell lines, including ovarian carcinoma, lung carcinoma, breast carcinoma, uterine sarcoma, leukemia and lymphoma, with IC50 values ranging from 40 to 940nM. AT7519 with concentration of 250-1000nM can induce G0-G1 and G2-M cell cycle blockade in HCT116 cells. Intraperitoneal or intravenous administration of 9.1mg/kg AT7519 twice a day for 9 consecutive days achieved completely tumor regression on day 15 in HCT116 tumor xenografts . Phase 2 studies of AT7519 treatment for mantle cell lymphoma and chronic lymphocytic leukemia have been completed (see in https://www.clinicaltrials.gov/). |
实验方案 | |||
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1mg | 5mg | 10mg | |
1 mM 5 mM 10 mM |
2.39mL 0.48mL 0.24mL |
11.94mL 2.39mL 1.19mL |
23.88mL 4.78mL 2.39mL |
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