A CDK inhibitor
Dinaciclib is a potent cyclin-dependent kinase (CDK) inhibitor with IC50s for CDK2, CDK5, CDK1 and CDK9 at 1 nM, 1 nM, 3 nM, and 4 nM, respectively. [1] It is in phase I or II clinical trials for various cancers.
Dinaciclib interacts with the acetyl-lysine recognition site of bromodomains. [2] Inhibition of CDK 1 suppresses Rb phosphorylation, leading to cell cycle arrest and apoptosis. [3]
Dinaciclib is active against a broad spectrum of human tumor cell lines in vitro and in vivo. It has great potential to improve cancer chemotherapy.
参考文献:
[1]Parry D., et al. (2010). Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor. Mol Cancer Ther (9): 2344- 2353.
[2]Martin, M. P., et al. (2013). Cyclin-dependent kinase inhibitor dinaciclib interacts with the acetyl-lysine recognition site of bromodomains. ACS Chemical Biology 8 (11): 2360–5.
[3]Payton M., et al. (2006). Discovery and Evaluation of Dual CDK1 and CDK2 Inhibitors. Cancer Res 66: 4299-4308.
| Kinase experiment [1]: | |
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Cyclin/CDK kinase assay |
Recombinant cyclin/CDK holoenzymes were purified from Sf9 cells engineered to produce baculoviruses that express a specific cyclin or CDK. Cyclin/CDK complexes were typically diluted to a final concentration of 50 μg/mL in a kinase reaction buffer containing 50 mmol/L Tris-HCl (pH 8.0), 10 mmol/L MgCl2, 1 mmol/L DTT, and 0.1 mmol/L sodium orthovanadate. For each kinase reaction, 1 μg of enzyme and 20 μL of a 2-μmol/L substrate solution (a biotinylated peptide derived from histone H1; Amersham) were mixed and combined with 10 μL of diluted SCH 727965. The reaction was started by the addition of 50 μL of 2 μmol/L ATP and 0.1 μCi of 33P-ATP. Kinase reactions were incubated for 1 hour at room temperature and were stopped by the addition of 0.1% Triton X-100, 1 mmol/L ATP, 5 mmol/L EDTA, and 5 mg/mL streptavidin-coated SPA beads. SPA beads were captured using a 96-well GF/B filter plate and a Filtermate universal harvester. Beads were washed twice with 2 mol/L NaCl and twice with 2 mol/L NaCl containing 1% phosphoric acid. The signal was then assayed using a Top-Count 96-well liquid scintillation counter. Dose-response curves were generated from duplicate, eight-point serial dilutions of inhibitory compounds. IC50 values were derived by nonlinear regression analysis. |
| Cell experiment [1]: | |
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Cell lines |
A2780 cells |
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Preparation method |
Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reaction Conditions |
2 h |
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Applications |
SCH 727965 significantly abrogates phosphorylation of Rb on Ser 807/811 at concentrations >6.25 nmol/L and also leads to the generation of the p85 PARP cleavage product. 100 nmol/L SCH727965 treatment for 2 hours is effective in inducing suppression of Rb phosphorylation and caspase activation which can be detected up to 6 hours later. |
| Animal experiment [1]: | |
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Animal models |
A2780 ovarian cancer mouse xenograft model |
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Dosage form |
i.p. administration at 8, 16, 32, and 48 mg/kg daily |
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Applications |
SCH 727965 i.p. administration at 8, 16, 32, and 48 mg/kg daily for 10 days shows tumor inhibitionby 70%, 70%, 89%, and 96%, respectively. SCH 727965 is also well tolerated, and the maximum body weight loss in the highest dosage group is 5%. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: 1. Parry D, Guzi T, Shanahan F et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010 Aug;9(8):2344-53. |
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