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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4 Customer Reviews

  • (a) Western blot for RALB-GTP, total RALB and GAPDH proteins in KG1 AML cells treated for 8 h with DMSO or dinaciclib (representative of three independent experiments).

    Oncogene, 2016. Dinaciclib (SCH727965) purchased from Selleck.

    CDK4/6 inhibition has potent cytostatic effect in HER2-positive models. The indicated cells were treated with PD-0332991 (1 uM) or Dinaciclib (1 uM) for 96 hours and plates were stained with crystal violet.

    Genes Cancer 2014 5(7-8), 261-72. Dinaciclib (SCH727965) purchased from Selleck.

  • (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.

    PLoS One, 2017, 12(2):e0172315 . Dinaciclib (SCH727965) purchased from Selleck.

    It is a viability curve of various cell lines treated the dinaciclib.

    Dinaciclib (SCH727965) purchased from Selleck.

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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 NH;2cWpCeG:ydH;zbZMhSXO|YYm= NFi5WWwyODBibl2= NYPz[|FsOjRiaB?= NUexbmhCcW6mdXPld{Bk\WyuIHP5Z4xmKGG{cnXzeC=> NFzidoczPTJ6OUi4Oy=>
Kasumi-1 M4m1b2Fxd3C2b4Ppd{BCe3OjeR?= NXnDZ45bOTByIH7N MlLWNlQhcA>? NXnueWVYcW6mdXPld{Bk\WyuIHP5Z4xmKGG{cnXzeC=> MV:yOVI5QTh6Nx?=
U937 M3:zPWZ2dmO2aX;uJGF{e2G7 M2H4XVIwPS9zMDDuUS=> NUXIc2xbOyCq M1jtdYJtd2OtczDpcoR2[3Srb36gc4YhYEKSLUHzJIFv\CCmb4fud5Rz\WGvIIThdodmfHN? NX60V5Z3OjR|NkK0OlU>
8226 NFLhXmlHfW6ldHnvckBCe3OjeR?= MnTpNk82NzFyIH7N NED4V|A1KGh? MmDwZoxw[2u|IHnu[JVkfGmxbjDv[kBZSlBvMYOgZY5lKGSxd37zeJJm[W1idHHy[4V1ew>? NYqzemZGOjR|NkK0OlU>
H929 MUfGeY5kfGmxbjDBd5NigQ>? NFPWN|czNzVxMUCgcm0> M4LhTVQhcA>? NXHCOYpu[myxY3vzJIlv\HWldHnvckBw\iC[QmCtNZMh[W6mIHTve45{fHKnYX2geIFz\2W2cx?= NHHVSJAzPDN4MkS2OS=>
K562 MV;GeY5kfGmxbjDBd5NigQ>? Mn;vNU42NzNxODDuUS=> MYW2JIg> NXTlcmdE[myxY3vzJIlv\HWldHnvckBw\iC[QmCtNZMh[W6mIHTve45{fHKnYX2geIFz\2W2cx?= MV[yOFM3OjR4NR?=
BaF3/Bcr-abl M{fkbGZ2dmO2aX;uJGF{e2G7 NGradHQyNjVxMz:4JI5O NUXUdpRsPiCq NVXFW2JZ[myxY3vzJIlv\HWldHnvckBw\iC[QmCtNZMh[W6mIHTve45{fHKnYX2geIFz\2W2cx?= NXTNWXQzOjR|NkK0OlU>
U937  NWDJPXZzTnWwY4Tpc44hSXO|YYm= MUWyM|ExKG6P NUGyR2pLOyCq M4ToVIJtd2OtczDpcoR2[3Srb36gc4YhYEKSLUHzJIFv\CCmb4fud5Rz\WGvIIThdodmfHN? MYSyOFM3OjR4NR?=
1205Lu M1jxbGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NWq2[pJJOTBxM{Cgcm0> M{i3ZlczKGh? NVX2[3lmcW6qaXLpeJMh[2WubDDndo94fGhiYX7kJJN2en[rdnHs MW[yN|UzPzJ{NR?=
WM1366 MkLVS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M3:zfVExNzNyIH7N M3Xwe|czKGh? NXHkdZFmcW6qaXLpeJMh[2WubDDndo94fGhiYX7kJJN2en[rdnHs NU\hS21vOjN3MkeyNlU>
RD M{L0WWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NILiS5RKSzVyPUiuNkBvVQ>? MmTuNlI{OTV{NEC=
Rh41 M3;DUWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHPOdIxKSzVyPUGwMlUhdk1? MWKyNlMyPTJ2MB?=
Rh18 MkLQS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NHLSe25KSzVyPUGwMlUhdk1? NEH2SoMzOjNzNUK0NC=>
Rh30 M1v2PGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NFXJNVlKSzVyPUmgcm0> MWWyNlMyPTJ2MB?=
BT-12 MVXHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NILRVG5KSzVyPUiuOUBvVQ>? NH3IPHIzOjNzNUK0NC=>
CHLA-266 MnPlS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? M{jEcWlEPTB;Nz6zJI5O M1rJUlIzOzF3MkSw
TC-71 Mn7oS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MXHJR|UxRTNwOTDuUS=> M{foblIzOzF3MkSw
CHLA-9 NYi5ZolLT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NX7Fb|RHUUN3ME24JI5O M1vFeVIzOzF3MkSw
CHLA-10 MnXOS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MVTJR|UxRTZwMzDuUS=> NGHOS5QzOjNzNUK0NC=>
CHLA-258 Mlr0S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NYnLVXNxUUN3ME25Mlkhdk1? M4exXFIzOzF3MkSw
GBM2 M2XwVWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NEn3VGVKSzVyPU[uOUBvVQ>? MXeyNlMyPTJ2MB?=
NB-1643 NWnPZ4QxT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= M1fsTWlEPTB;Mz6zJI5O NFTyd4EzOjNzNUK0NC=>
NB-EBc1 NIezdmZIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= MorYTWM2OD15IH7N M{CxXlIzOzF3MkSw
CHLA-90 Mle3S5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? NUf5OJVYUUN3ME23MlUhdk1? MmHzNlI{OTV{NEC=
CHLA-136 MlPvS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MkPtTWM2OD17Lkigcm0> MYWyNlMyPTJ2MB?=
NALM-6 M{X0UGdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NUO5Xm03UUN3ME20MlYhdk1? M3TVVVIzOzF3MkSw
COG-LL-317 NUfndItUT3Kxd4ToJGlvcGmkaYTpc44hSXO|YYm= NIPwUIxKSzVyPU[uOUBvVQ>? M4PwdlIzOzF3MkSw
RS4;11 MUnHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? NV32d2VKUUN3ME21MlEhdk1? M2jWeFIzOzF3MkSw
MOLT-4 NFjSWVBIem:5dHigTY5pcWKrdHnvckBCe3OjeR?= NH:2VFBKSzVyPUmuN{BvVQ>? M{\IeFIzOzF3MkSw
CCRF-CEM M{fLXWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NHTDeIVKSzVyPUWuOkBvVQ>? NX25ZoNKOjJ|MUWyOFA>
Kasumi-1 M{S1RWdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NIPTWnVKSzVyPUSuOUBvVQ>? MUSyNlMyPTJ2MB?=
Karpas-299 MlzpS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MlnxTWM2OD1|Lkmgcm0> MoHHNlI{OTV{NEC=
Ramos-RA1 MoPxS5Jwf3SqIFnubIljcXSrb36gRZN{[Xl? MWTJR|UxRTdwOTDuUS=> MoqxNlI{OTV{NEC=
MIAPaCa-2 MVjHdo94fGhiSX7obYJqfGmxbjDBd5NigQ>? MoPoO|IhcA>? NF7QOFhIUTVyPUGwJI5O NGfVdpMzOTd4OEe3PS=>
Pa20C  M1rTRmdzd3e2aDDJcohq[mm2aX;uJGF{e2G7 NGGyNIg4OiCq NHrWUopIUTVyPUKwJI5O NID0e4YzOTd4OEe3PS=>
ML-1 NF;lOIdCeG:ydH;zbZMhSXO|YYm= MlfwNU0yODByIH7N MkXBOEBp MYLpcoR2[2W|IHHwc5B1d3OrczDzcIlocHSueR?= M{\SWVIyPzZ6N{e3

... Click to View More Cell Line Experimental Data

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]
+ Expand

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]
+ Expand
  • 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]
+ Expand
  • 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 individually and in order:
2% DMSO+30% PEG 300+ddH2O
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
Synonyms PS-095760

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01676753 Active, not recruiting Advanced or Metastatic Breast Cancer|Triple Negative Breast Cancer Jo Chien|Merck Sharp & Dohme Corp.|University of California, San Francisco June 2016 Phase 1|Phase 2
NCT02684617 Recruiting rrCLL|rrMM|rrDLBCL Merck Sharp & Dohme Corp. March 2016 Phase 1
NCT01783171 Active, not recruiting Pancreatic Adenocarcinoma|Recurrent Pancreatic Carcinoma|Stage III Pancreatic Cancer|Stage IV Pancreatic Cancer|Unresectable Pancreatic Carcinoma National Cancer Institute (NCI) January 2013 Phase 1
NCT01711528 Active, not recruiting Recurrent Plasma Cell Myeloma National Cancer Institute (NCI) December 2012 Phase 1
NCT01650727 Completed Chronic Lymphocytic Leukemia|Small Lymphocytic Lymphoma Merck Sharp & Dohme Corp. October 2012 Phase 1
NCT01624441 Active, not recruiting Estrogen Receptor Negative|HER2/Neu Negative|Male Breast Carcinoma|Progesterone Receptor Negative|Recurrent Breast Carcinoma|Stage IV Breast Cancer|Triple-Negative Breast Carcinoma National Cancer Institute (NCI) August 2012 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.

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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.

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID