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Purity: =99.20%
Dinaciclib (formerly known as PS-095760, SCH727965; PS 095760; SCH 727965) is a novel, selective and potent cyclin-dependent kinases (CDK) inhibitor with potential antineoplastic activity. In cell-free assays, it inhibits CDK2, CDK5, CDK1, and CDK9 with IC50s of 1 nM, 1 nM, 3 nM, and 4 nM, respectively. Additionally, dinaciclib prevents the incorporation of thymidine (dThd) into DNA and may have anticancer properties. Dinaciclib has better therapeutic index and shows better activity than flavopiridol. In a variety of mouse models, dinaciclib caused the regression of solid tumors that had already grown after doses were periodically scheduled below the level that was maximally tolerated.
| Targets |
CDK2 (IC50 = 1 nM); CDK5 (IC50 = 1 nM); CDK1 (IC50 = 3 nM); CDK9 (IC50 = 4 nM)
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| ln Vitro |
Dinaciclib is another strong inhibitor of DNA replication that, at an IC50 of 4 nM, prevents the thymidine (dThd) DNA from being incorporated into A2780 cells. At concentrations greater than 6.25 nM, dinaciclib significantly inhibits the phosphorylation of Rb on Ser 807/811, which is consistent with the finding that in the same cell model, 4 nM concentrations are necessary to inhibit dThd DNA incorporation 50% of the time. The appearance of the p85 PARP cleavage product in cells exposed to >6.25 nM Dinaciclib indicates a significant correlation between the onset of apoptosis and complete suppression of Rb phosphorylation. Dinaciclib exhibits efficacy against a wide range of tumor cell lines in humans. In a dose-dependent manner, the addition of Dinaciclib during hydroxyurea exposure also suppresses the accumulation of γ-H2AX. [2] Dinaciclib causes a large-scale apoptosis in melanoma cells by suppressing their ability to proliferate. [3] Several osteosarcoma cell lines, including those resistant to dasatinib and doxorubicin, undergo apoptosis when exposed to dinaciclib. The phosphorylation of CDK inhibitor p27Kip1 at threonine 187 and RNAP II at serine 2 are both attenuated by dinaciclib. At 12 to 40 nM Dinaciclib, phosphorylation activity decreases (4 to 16 hours after Dinaciclib addition). Moreover, dinaciclib lowers Rb's phosphorylation at serine 807/811. Similar levels of apoptosis are induced in mock- and p53-depleted U2OS cells by dinaciclib.[4]
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| ln Vivo |
Tumor inhibition occurs at 70%, 70%, 89%, and 96%, respectively, after administering dinaciclib intraperitoneally (i.p.) at 8, 16, 32, and 48 mg/kg daily for ten days. The minimal effective dose (MED) of dinaciclib seems to be less than 8 mg/kg. Dinaciclib is well tolerated; in the highest dosage group, there is a maximum 5% reduction in body weight. In vivo, dinaciclib exhibits dose-dependent antitumor activity, with nearly total inhibition of tumor growth occurring at a dose level below the maximum tolerated dose (MTD). Dinaciclib in mice has a brief half-life in the plasma.[1]
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| Enzyme Assay |
Recombinant cyclin/CDK holoenzymes are isolated from Sf9 cells that have been modified to generate baculoviruses expressing a particular CDK or cyclin. Usually, cyclin/CDK complexes are diluted to a final concentration of 50 μg/mL in a kinase reaction buffer that has 0.1 mM sodium orthovanadate, 10 mM MgCl2, 1 mM DTT, and 50 mM Tris-HCl (pH 8.0) in it. In every kinase reaction, 10 μL of diluted Dinaciclib (SCH 727965) is mixed with 1 μg of enzyme and 20 μL of a 2 μM substrate solution (a biotinylated peptide derived from histone H1). The addition of 0.1 μCi of 33P-ATP and 50 μL of 2 μM ATP initiates the reaction. The addition of 0.1% Triton X-100, 1 mM ATP, 5 mM EDTA, and 5 mg/mL streptavidin-coated SPA beads stops the kinase reactions after an hour of room temperature incubation. A Filtermate universal harvester in combination with a 96-well GF/B filter plate is used to collect SPA beads. Two M NaCl and two M NaCl containing 1% phosphoric acid are used to wash the beads twice. A TopCount 96-well liquid scintillation counter is then used to measure the signal. Two sets of eight-point serial dilutions of inhibitory compounds are used to create dose-response curves. Nonlinear regression analysis is used to derive IC50 values.
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| Cell Assay |
Plated A2780 cells are grown using the proper growth media in tissue culture dishes. Growing cultures are subjected, usually for seven days, to varying concentrations of Dinaciclib (0.75, 1.5, 3.15, 6.25, 12.5, 25, and 500 nM) or a vehicle control. Once the medium is removed, cells are fixed for five minutes using a 50% methanol/50% acetone solution and then stained for five minutes using a 0.2% crystal violet solution in 2% ethanol. Water (5–10 mL) is used to wash the cells after staining them. 1% deoxycholic acid is used to solubilize stained cells, and a SOFTmax PRO 4.3 plate reader is used to measure the absorbance of the resultant solution at 600 nm. Plotting the absorbance of samples treated with Dinaciclib as a percentage of a vehicle-treated control is done, and the results are presented as an IC50 value in relation to these controls. The alamarBlue Cell Viability Assay kit is utilized to obtain cell viability assessments for suspension cell lines.
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| Animal Protocol |
Mice: Certain cell lines are grown in vitro, once they have been washed with PBS, they are resuspended in 50% Matrigel in PBS until they reach a final concentration of 4×107 to 5×107 cells per milliliter for tumor implantation. 0.1 mL of this suspension is subcutaneously injected into the flanks of naked mice. Every mouse has its tumor measured twice a week using a caliper to determine its length (L), width (W), and height (H). The tumor volume is then determined by applying the formula (L×W×H)/2. The animals are randomized to treatment groups (10 mice/group) when the tumor volume reaches 100 mm3. They are then given individual chemotherapeutic agents or Dinaciclib (8, 16, 32, and 48 mg/kg daily, i.p.) in accordance with the dosing schedule shown in the table and figure legends. Body weights and tumor volumes are measured both during and after treatment.
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| References |
| Molecular Formula |
C21H28N6O2
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| Molecular Weight |
396.49
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| Exact Mass |
396.23
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| Elemental Analysis |
C, 63.62; H, 7.12; N, 21.20; O, 8.07
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| CAS # |
779353-01-4
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| Related CAS # |
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| Appearance |
white solid powder
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| SMILES |
CCC1=C2N=C(C=C(N2N=C1)NCC3=C[N+](=CC=C3)[O-])N4CCCC[C@H]4CCO
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| InChi Key |
PIMQWRZWLQKKBJ-SFHVURJKSA-N
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| InChi Code |
InChI=1S/C21H28N6O2/c1-2-17-14-23-27-19(22-13-16-6-5-9-25(29)15-16)12-20(24-21(17)27)26-10-4-3-7-18(26)8-11-28/h5-6,9,12,14-15,18,22,28H,2-4,7-8,10-11,13H2,1H3/t18-/m0/s1
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| Chemical Name |
2-[(2S)-1-[3-ethyl-7-[(1-oxidopyridin-1-ium-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]piperidin-2-yl]ethanol
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5221 mL | 12.6107 mL | 25.2213 mL | |
| 5 mM | 0.5044 mL | 2.5221 mL | 5.0443 mL | |
| 10 mM | 0.2522 mL | 1.2611 mL | 2.5221 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01434316 | Active Recruiting |
Drug: Dinaciclib Drug: Veliparib |
Advanced Malignant Solid Neoplasm |
National Cancer Institute (NCI) |
November 1, 2011 | Phase 1 |
| NCT00937937 | Active Recruiting |
Drug: Dinaciclib | Mucosal Melanoma Recurrent Melanoma |
National Cancer Institute (NCI) |
Phase 2 | |
| NCT01624441 | Completed | Drug: Epirubicin Hydrochloride Drug: Dinaciclib |
Male Breast Carcinoma HER2/Neu Negative |
UNational Cancer Institute (NCI) |
August 21, 2012 | Phase 1 |
| NCT00871663 | Completed | Drug: SCH 727965 | Solid Tumors Multiple Myeloma |
Merck Sharp & Dohme LLC | August 2006 | Phase 1 |
| NCT00871910 | Completed | Drug: SCH 727965 Drug: Aprepitant |
Solid Tumors Multiple Myeloma |
Merck Sharp & Dohme LLC | October 11, 2006 | Phase 1 |
 Cyclin dependent kinase inhibitor SCH727965 reduces growth, colony formation and motility of pancreatic cancer cells in vitro.Cancer Biol Ther.2011 Oct 1;12(7):598-609. |
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 Spectrum of in vivo growth inhibition by SCH727965 in a panel of ten subcutaneous low-passage pancreatic cancer xenografts.Cancer Biol Ther.2011 Oct 1;12(7):598-609. |
 Combination treatment of orthotopic pancreatic cancer xenografts with SCH727965 and gemcitabine. Modified Boyden chamber assays show decreased in vitro cell motility of Pa20C cells after treatment with SCH727965 for 72 h.Cancer Biol Ther.2011 Oct 1;12(7):598-609. |
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