Dinaciclib (SCH727965)

Catalog No.S2768 Synonyms: PS-095760

Dinaciclib (SCH727965) Chemical Structure

Molecular Weight(MW): 396.49

Dinaciclib (SCH727965) is a novel and potent CDK inhibitor for CDK2, CDK5, CDK1 and CDK9 with IC50 of 1 nM, 1 nM, 3 nM and 4 nM in cell-free assays, respectively. It also blocks thymidine (dThd) DNA incorporation. Phase 3.

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Cited by 47 Publications

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Biological Activity

Description Dinaciclib (SCH727965) is a novel and potent CDK inhibitor for CDK2, CDK5, CDK1 and CDK9 with IC50 of 1 nM, 1 nM, 3 nM and 4 nM in cell-free assays, respectively. It also blocks thymidine (dThd) DNA incorporation. Phase 3.
Targets
CDK2 [1]
(Cell-free assay)		 CDK5 [1]
(Cell-free assay)		 CDK1 [1]
(Cell-free assay)		 CDK9 [1]
(Cell-free assay)
1 nM 1 nM 3 nM 4 nM
In vitro

Dinaciclib is also a potent DNA replication inhibitor that blocks thymidine (dThd) DNA incorporation in A2780 cells with IC50 of 4 nM. Dinaciclib strongly suppresses phosphorylation of Rb on Ser 807/811 at concentrations >6.25 nM, which is in agreement with the observation that 4 nM concentrations are required for 50% inhibition of dThd DNA incorporation in the same cell model. Significantly, complete suppression of Rb phosphorylation is correlated with the onset of apoptosis, as indicated by the appearance of the p85 PARP cleavage product in cells exposed to >6.25 nM Dinaciclib. Dinaciclib is active against a broad spectrum of human tumor cell lines. [1] Addition of Dinaciclib during hydroxyurea exposure also suppresses accumulation of γ-H2AX, in a dose-dependent manner. [2] Dinaciclib inhibits melanoma cell proliferation, and drives melanoma cells into massive apoptosis. [3] Dinaciclib induces the apoptosis of several osteosarcoma cell lines including those resistant to doxorubicin and dasatinib. Dinaciclib attenuates the phosphorylation of RNAP II at serine 2 and the phosphorylation of the CDK inhibitor p27Kip1 at threonine 187. Reductions in phosphorylation activity occurrs at 12 - 40 nM Dinaciclib (4 to 16 hours post-Dinaciclib addition). Dinaciclib also reduces the phosphorylation of Rb at serine 807/811. Dinaciclib induces the apoptosis of mock- and p53-depleted U2OS cells to a similar extent. [4]
Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
CA46 MmLrRZBweHSxc3nzJGF{e2G7 MVexNFAhdk1? MYiyOEBp M3z6[olv\HWlZYOgZ4VtdCCleXPs[UBienKnc4S= MkDoNlUzQDl6OEe=
Kasumi-1 MkDrRZBweHSxc3nzJGF{e2G7 NITDPVAyODBibl2= Mn7FNlQhcA>? NXLhcGx{cW6mdXPld{Bk\WyuIHP5Z4xmKGG{cnXzeC=> NF7GZ|gzPTJ6OUi4Oy=>
U937 MUjGeY5kfGmxbjDBd5NigQ>? NHrhVWozNzVxMUCgcm0> MUKzJIg> MYficI9kc3NiaX7keYN1cW:wIH;mJHhDWC1zczDhcoQh\G:5boP0doVidSC2YYLn[ZR{ NGDwO3gzPDN4MkS2OS=>
8226 MXLGeY5kfGmxbjDBd5NigQ>? M2DSUFIwPS9zMDDuUS=> MoS2OEBp M2jQeYJtd2OtczDpcoR2[3Srb36gc4YhYEKSLUHzJIFv\CCmb4fud5Rz\WGvIIThdodmfHN? M4fWb|I1OzZ{NE[1
H929 NH;YWpFHfW6ldHnvckBCe3OjeR?= MXGyM|UwOTBibl2= NVjyfpE6PCCq NVHyTWEy[myxY3vzJIlv\HWldHnvckBw\iC[QmCtNZMh[W6mIHTve45{fHKnYX2geIFz\2W2cx?= M4nDdlI1OzZ{NE[1
K562 NI\XTnVHfW6ldHnvckBCe3OjeR?= MoXQNU42NzNxODDuUS=> NXrXdnJMPiCq MVricI9kc3NiaX7keYN1cW:wIH;mJHhDWC1zczDhcoQh\G:5boP0doVidSC2YYLn[ZR{ M1PK[|I1OzZ{NE[1
BaF3/Bcr-abl NHnWTodHfW6ldHnvckBCe3OjeR?= NX\6PIZKOS53L{OvPEBvVQ>? NInZSZk3KGh? NEDXcY1jdG:la4OgbY5lfWO2aX;uJI9nKFiEUD2xd{BidmRiZH;3cpN1emWjbTD0ZZJo\XS| NFTJZ4ozPDN4MkS2OS=>
U937  MVHGeY5kfGmxbjDBd5NigQ>? NYToV5R3Oi9zMDDuUS=> M{nwRlMhcA>? M1v4TIJtd2OtczDpcoR2[3Srb36gc4YhYEKSLUHzJIFv\CCmb4fud5Rz\WGvIIThdodmfHN? M3XXe|I1OzZ{NE[1
1205Lu M2XzOmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3K0UVExNzNyIH7N NEP0[ZY4OiCq MofzbY5pcWKrdIOgZ4VtdCCpcn;3eIgh[W6mIIP1dpZqfmGu MV[yN|UzPzJ{NR?=
WM1366 NIfsO5JIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NYjhT2ZpOTBxM{Cgcm0> M3HRbVczKGh? NV;0OIR[cW6qaXLpeJMh[2WubDDndo94fGhiYX7kJJN2en[rdnHs M4XVOFI{PTJ5MkK1
RD M2L0Nmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M3rJTWlEPTB;OD6yJI5O MkDWNlI{OTV{NEC=
Rh41 NVHBXXdFT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NFL1OGVKSzVyPUGwMlUhdk1? MkfLNlI{OTV{NEC=
Rh18 MnnOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{LXZmlEPTB;MUCuOUBvVQ>? MoPxNlI{OTV{NEC=
Rh30 MVvHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1vqdWlEPTB;OTDuUS=> NV7G[ZZyOjJ|MUWyOFA>
BT-12 NUnUeotFT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MVvJR|UxRThwNTDuUS=> NGe1cFYzOjNzNUK0NC=>
CHLA-266 MYrHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MkTSTWM2OD15LkOgcm0> MYmyNlMyPTJ2MB?=
TC-71 M1;EfWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 MkPqTWM2OD1|Lkmgcm0> NU\TWos{OjJ|MUWyOFA>
CHLA-9 NXfqRpZxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NITKflZKSzVyPUigcm0> M4PiZlIzOzF3MkSw
CHLA-10 NV\yOGZ7T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MkLsTWM2OD14LkOgcm0> NFLH[GozOjNzNUK0NC=>
CHLA-258 NYDZcphGT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1jFNmlEPTB;OT65JI5O NUTRcoJLOjJ|MUWyOFA>
GBM2 M{HFeWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NH7FcWZKSzVyPU[uOUBvVQ>? MXiyNlMyPTJ2MB?=
NB-1643 NEnkdIdIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M2\SNmlEPTB;Mz6zJI5O NXzvfWNqOjJ|MUWyOFA>
NB-EBc1 NXTZRoxQT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MkTOTWM2OD15IH7N NXfM[JhxOjJ|MUWyOFA>
CHLA-90 MoHSS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MX3JR|UxRTdwNTDuUS=> MX6yNlMyPTJ2MB?=
CHLA-136 MXTHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? M1zSNWlEPTB;OT64JI5O MUeyNlMyPTJ2MB?=
NALM-6 M2fuUmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 M4TzN2lEPTB;ND62JI5O MUGyNlMyPTJ2MB?=
COG-LL-317 Ml7MS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MU\JR|UxRTZwNTDuUS=> NH3BeWczOjNzNUK0NC=>
RS4;11 MYLHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MYrJR|UxRTVwMTDuUS=> MmLyNlI{OTV{NEC=
MOLT-4 NUnzXWNLT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NV7ob3l7UUN3ME25MlMhdk1? NYnLPXQ1OjJ|MUWyOFA>
CCRF-CEM NVPKW|N7T3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MYHJR|UxRTVwNjDuUS=> NHTufI4zOjNzNUK0NC=>
Kasumi-1 NETZSnlIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= M1\jWWlEPTB;ND61JI5O MmDZNlI{OTV{NEC=
Karpas-299 MnnKS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{HLcWlEPTB;Mz65JI5O NH\qVJczOjNzNUK0NC=>
Ramos-RA1 NX3ufmdbT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= MUfJR|UxRTdwOTDuUS=> NIq5dowzOjNzNUK0NC=>
MIAPaCa-2 MVnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NWX0c2d3PzJiaB?= MYnHTVUxRTFyIH7N MmrCNlE4Pjh5N{m=
Pa20C  NVfyOmpsT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NEHtfVA4OiCq NUKzTmVWT0l3ME2yNEBvVQ>? M13oWVIyPzZ6N{e5
ML-1 MkfjRZBweHSxc3nzJGF{e2G7 M3zTO|EuOTByMDDuUS=> MoL2OEBp MmCxbY5lfWOnczDhdI9xfG:|aYOgd4xq\2i2bIm= MUWyNVc3QDd5Nx?=

... Click to View More Cell Line Experimental Data
Assay
Methods Test Index PMID
Western blot
Mcl-1 / Bcl-2 / Bcl-xl / Bax / Bak / PUMA / Noxa; 

PubMed: 28714472     


H196 cells treated with doxorubicin for the indicated times were assessed by immunoblot analysis. 

Cleaved PARP / c-Myc; 

PubMed: 25289887     


Immunoblot analysis of A2780 cells during the 5 hr time-course treatment of Dinaciclib (100 nM).

Survivin; 

PubMed: 28207834     


Western blot analysis was performed in cells treated with dinaciclib (25 nM) or vehicle for the indicated time. The levels of Mcl-1, Bcl-xL and survivin were evaluated in BHP7-13, WRO82-1 and 8505C cells.

RNAP II (P-Ser2/P-Ser5); 

PubMed: 25289887     


Immunoblot analysis of A2780 cells during the 5 hr time-course treatment of Dinaciclib (100 nM).

28714472 25289887 28207834
Growth inhibition assay
Cell viability; 

PubMed: 27378523     


(a) Six typical NB cell lines were treated with increasing concentrations of dinaciclib for 48 hrs. Cell viability was then measured by the Cell Counting Kit-8 (CCK-8) assay. P-values < 0.01 (**) or P < 0.001 (***) (Student's t-test, two-tailed) were indicated. (b) The IC50 values of dinaciclib on each cell line listed were calculated based on the data in (a).

Cell viability; 

PubMed: 28361959     


(a-c) The number of cells after dinaciclib treatment. Cell number in 49 fields (7 × 7) was calculated and shown in the graph (n = 4). (a) Total cell number. **p < 0.01 vs control. (b) Number of OCT4 positive cells. **p < 0.01 vs control. (c) Number of OCT4 negative cells. n.s., not significant. (d) The percentage of OCT4 positive cells. **p < 0.01 vs control. *p < 0.05 vs 6 nM.

27378523 28361959
Immunofluorescence
cyclin B1 / α-tubulin / Aurora A; 

PubMed: 28207834     


(B) Cells were treated with dinaciclib (25 nM) or placebo for 24 h and stained with fluorescent antibodies against DAPI (blue), cyclin B1 (red) and α-tubulin (green). Cyclin B1 level was significantly reduced after treatment of dinaciclib in prophase cells of BHP7-13, WRO82-1 and 8505C. (C) Cells were treated with dinaciclib (25 nM) or placebo for 24 h and stained with fluorescent antibodies against DAPI (blue), Aurora A (red) and α-tubulin (green). Aurora A level was significantly reduced after treatment of dinaciclib in BHP7-13, WRO82-1 and 8505C cells in prophase. Scale bar, 10 μm.

OCT4; 

PubMed: 28361959     


Representative images of OCT4 positive cells (red). Nuclei were stained with Hoechst (blue). Scale bars = 200 μm.

28207834 28361959
In vivo Dinaciclib i.p. administration at 8, 16, 32, and 48 mg/kg daily for 10 days results in tumor inhibition by 70%, 70%, 89%, and 96%, respectively. Dinaciclib MED (minimum effective dose) appears to be <8 mg/kg. Dinaciclib is well tolerated, and the maximum body weight loss in the highest dosage group is 5%. Dinaciclib has dose-dependent antitumor activity in vivo, and that nearly complete inhibition of tumor growth occurs at a dose level below the MTD (maximum tolerated dose). Dinaciclib has a short plasma half-life in mouse. [1]

Protocol

Kinase Assay:[1]
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Cyclin/CDK kinase assay:

Recombinant cyclin/CDK holoenzymes are purified from Sf9 cells engineered to produce baculoviruses that express a specific cyclin or CDK. Cyclin/CDK complexes are typically diluted to a final concentration of 50 μg/mL in a kinase reaction buffer containing 50 mM Tris-HCl (pH 8.0), 10 mM MgCl2, 1 mM DTT, and 0.1 mM sodium orthovanadate. For each kinase reaction, 1 μg of enzyme and 20 μL of a 2-μM substrate solution (a biotinylated peptide derived from histone H1) are mixed and combined with 10 μL of diluted Dinaciclib. The reaction is started by the addition of 50 μL of 2 μM ATP and 0.1 μCi of 33P-ATP. Kinase reactions are incubated for 1 hour at room temperature and are stopped by the addition of 0.1% Triton X-100, 1 mM ATP, 5 mM EDTA, and 5 mg/mL streptavidin-coated SPA beads. SPA beads are captured using a 96-well GF/B filter plate and a Filtermate universal harvester. Beads are washed twice with 2 M NaCl and twice with 2 M NaCl containing 1% phosphoric acid. The signal is then assayed using a TopCount 96-well liquid scintillation counter.
Cell Research:[1]
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  • Cell lines: A2780 cells
  • Concentrations: 0 μM -5 μM
  • Incubation Time: 24 hours
  • Method: A2780 cells are maintained in DMEM plus 10% fetal bovine serum and passaged twice weekly by detaching the monolayer with trypsin-EDTA. One hundred microliters of A2780 cells (5 × 103 cells) are added per well to a 96-well Cytostar-T plate and incubated for 16 hours to 24 hours at 37 °C. Dinaciclib is serially diluted in complete media plus 2% 14C-labeled dThd. Media are removed from the Cytostar T plate; 200 μL of various Dinaciclib dilutions are added in quadruplicate; and the cells are incubated for 24 hours at 37 °C. Accumulated incorporation of radiolabel is assayed using scintillation proximity and measured on a TopCounTM.
    (Only for Reference)
Animal Research:[1]
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  • Animal Models: Nude mice bearing A2780 tumors
  • Formulation: 20% hydroxypropyl-β-cyclodextran
  • Dosages: 8 mg/kg, 16 mg/kg, 32 mg/kg, and 48 mg/kg
  • Administration: Administered via i.p.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 26 mg/mL warmed (65.57 mM)
Ethanol 8 mg/mL warmed (20.17 mM)
Water Insoluble
In vivo Add solvents to the product individually and in order(Data is from Selleck tests instead of citations):
2% DMSO+30% PEG 300+ddH2O
For best results, use promptly after mixing. 		10mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 396.49
Formula

C21H28N6O2
CAS No. 779353-01-4
Storage powder
in solvent
Synonyms PS-095760

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Clinical Trial Information

NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT03484520 Recruiting Drug: Venetoclax|Drug: Dinaciclib Cancer - Acute Myeloid Leukemia AbbVie|Merck Sharp & Dohme Corp. July 23 2018 Phase 1
NCT01434316 Recruiting Drug: Dinaciclib|Drug: Veliparib Advanced Malignant Solid Neoplasm National Cancer Institute (NCI) November 1 2011 Phase 1

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

Handling Instructions

Tel: +1-832-582-8158 Ext:3

If you have any other enquiries, please leave a message.

  • * Indicates a Required Field

Frequently Asked Questions

  • Question 1:

    I want to know how to reconstitute the inhibitor for in vivo studies?

  • Answer:

    S2768 (SCH727965) in 15% Captisol at 8 mg/ml is a suspension for oral administration. And it can be dissolved in 2% DMSO/30% PEG 300/ddH2O at 10 mg/ml as a clear solution for injection.

selleck catalog

CDK Signaling Pathway Map

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  • Palbociclib (PD0332991) Isethionate

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID