Dinaciclib - CAS 779353-01-4
Catalog number: B0084-454920
Category: Inhibitor
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Molecular Formula:
C21H28N6O2
Molecular Weight:
396.49
COA:
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Targets:
CDK
Description:
Dinaciclib, also known as SCH727965, is a potent CDK inhibitor with potential antineoplastic activity. Dinaciclib selectively inhibits cyclin dependent kinases CDK1, CDK2, CDK5, and CDK9 activity in vitro with IC(50) values of 1, 1, 3, and 4 nmol/L, respectively. Compared with flavopiridol, Dinaciclib exhibits superior activity with an improved therapeutic index. Dinaciclib induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level.
Ordering Information
Catalog Number Size Price Stock Quantity
B0084-454920 25 mg $199 In stock
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Appearance:
White Solid Powder
Synonyms:
SCH 727965; SCH727965; SCH-727965; PS095760; PS 095760; PS-095760; Dinaciclib. 2-[(2S)-1-[3-ethyl-7-[(1-oxidopyridin-1-ium-3-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]piperidin-2-yl]ethanol
MSDS:
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InChIKey:
PIMQWRZWLQKKBJ-SFHVURJKSA-N
InChI:
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
Canonical SMILES:
CCC1=C2N=C(C=C(N2N=C1)NCC3=C[N+](=CC=C3)[O-])N4CCCCC4CCO
Current Developer:
Schering-Plough/Merck
1.A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition.
Alagpulinsa DA1, Ayyadevara S1, Yaccoby S2, Shmookler Reis RJ3. Mol Cancer Ther. 2016 Feb;15(2):241-50. doi: 10.1158/1535-7163.MCT-15-0660. Epub 2015 Dec 30.
PARP1/2 are required for single-strand break repair, and their inhibition causes DNA replication fork collapse and double-strand break (DSB) formation. These DSBs are primarily repaired via homologous recombination (HR), a high-fidelity repair pathway. Should HR be deficient, DSBs may be repaired via error-prone nonhomologous end-joining mechanisms, or may persist, ultimately resulting in cell death. The combined disruption of PARP and HR activities thus produces synthetic lethality. Multiple myeloma cells are characterized by chromosomal instability and pervasive DNA damage, implicating aberrant DNA repair. Cyclin-dependent kinases (CDK), upstream modulators of HR, are dysregulated in multiple myeloma. Here, we show that a CDK inhibitor, dinaciclib, impairs HR repair and sensitizes multiple myeloma cells to the PARP1/2 inhibitor ABT-888. Dinaciclib abolishes ABT-888-induced BRCA1 and RAD51 foci and potentiates DNA damage, indicated by increased γH2AX foci.
2.Dinaciclib, a Cyclin-Dependent Kinase Inhibitor Promotes Proteasomal Degradation of Mcl-1 and Enhances ABT-737-Mediated Cell Death in Malignant Human Glioma Cell Lines.
Jane EP1, Premkumar DR2, Cavaleri JM1, Sutera PA1, Rajasekar T1, Pollack IF2. J Pharmacol Exp Ther. 2016 Feb;356(2):354-65. doi: 10.1124/jpet.115.230052. Epub 2015 Nov 19.
The prognosis for malignant glioma, the most common brain tumor, is still poor, underscoring the need to develop novel treatment strategies. Because glioma cells commonly exhibit genomic alterations involving genes that regulate cell-cycle control, there is a strong rationale for examining the potential efficacy of strategies to counteract this process. In this study, we examined the antiproliferative effects of the cyclin-dependent kinase inhibitor dinaciclib in malignant human glioma cell lines, with intact, deleted, or mutated p53 or phosphatase and tensin homolog on chromosome 10; intact or deleted or p14ARF or wild-type or amplified epidermal growth factor receptor. Dinaciclib inhibited cell proliferation and induced cell-cycle arrest at the G2/M checkpoint, independent of p53 mutational status. In a standard 72-hour 3-[4,5-dimethylthiazol- 2yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H, tetrazolium (MTS) assay, at clinically relevant concentrations, dose-dependent antiproliferative effects were observed, but cell death was not induced.
3.The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia.
Baker A1, Gregory GP2, Verbrugge I3, Kats L1, Hilton JJ4, Vidacs E4, Lee EM5, Lock RB5, Zuber J6, Shortt J7, Johnstone RW8. Cancer Res. 2016 Mar 1;76(5):1158-69. doi: 10.1158/0008-5472.CAN-15-1070. Epub 2015 Dec 1.
Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis.
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CAS 779353-01-4 Dinaciclib

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