Pyrazolo[1,5-<i>a</i>]-1,3,5-triazine as a Purine Bioisostere: Access to Potent Cyclin-Dependent Kinase Inhibitor (<i>R</i>)-Roscovitine Analogue

Popowycz, Florence; Fournet, Guy; Schneider, Cédric; Bettayeb, Karima; Ferandin, Yoan; Lamigeon, Cyrile; Tirado, Óscar M.; Mateo-Lozano, Silvia; Notario, Vicente; Colas, Pierre; Bernard, Philippe; Meijer, Laurent; Joseph, Benoı̂t

doi:10.1021/jm801340z

Cited by 65 publications

(55 citation statements)

References 41 publications

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“…MYCN down-regulation was also induced by CDK inhibitors other than CR8 and roscovitine (Figure 6): MR4 (unpublished), N-&-N1 (23, 24), purvalanol A (57), SCH727965 (58), AT7519 (59), SNS-032 (60) and flavopiridol (61), but not by N6-methyl-CR8 and N6-methylroscovitine (the kinase inactive derivatives of CR8 and roscovitine, respectively) (35). Besides CDKs, roscovitine and CR8 interact with a few other kinases as shown above and earlier (20, 34, 35).…”

Section: Resultsmentioning

confidence: 99%

“…Among the first CDK inhibitors are the purines olomoucine, roscovitine, purvalanol, and their analogues (reviews in 14, 19). The most recent analogues include (S)-CR8 (20-22), N-&-N1 (23, 24), and others (25-28). (R)-roscovitine (CYC202 or Seliciclib) is currently in late phase 2 clinical trial against NSC lung cancer, breast and nasopharyngeal cancer (29-33).…”

Section: Introductionmentioning

confidence: 99%

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CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells

et al. 2013

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To understand the mechanisms of action of (R)-roscovitine and (S)-CR8, two related pharmacological inhibitors of cyclin-dependent kinases (CDKs), we applied a variety of ‘-omics’ techniques to the human neuroblastoma SH-SY5Y and IMR32 cell lines: [1] kinase interaction assays, [2] affinity competition on immobilized broad-spectrum kinase inhibitors, [3] affinity chromatography on immobilized (R)-roscovitine and (S)-CR8, [4] whole genome transcriptomics analysis and specific quantitative PCR studies, [5] global quantitative proteomics approach and Western blot analysis of selected proteins. Altogether the results show that the major direct targets of these two molecules belong to the CDKs (1, 2, 5, 7, 9, 12), DYRKs, CLKs, CK1s families. By inhibiting CDK7, CDK9 and CDK12, these inhibitors transiently reduce RNA polymerase 2 activity, which results in down-regulation of a large set of genes. Global transcriptomics and proteomics analysis converge to a central role of MYC transcription factors down-regulation. Indeed CDK inhibitors trigger rapid and massive down-regulation of MYCN expression in MYCN amplified neuroblastoma cells as well as in nude mice xenografted IMR32 cells. Inhibition of casein kinase 1 may also contribute to the antitumoral activity of (R)-roscovitine and (S)-CR8. This dual mechanism of action may be crucial in the use of these kinase inhibitors for the treatment of MYC-dependent cancers, in particular neuroblastoma where MYCN amplification is a strong predictor factor for high-risk disease.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells

et al. 2013

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“…Seventy-five structurally diverse CDK9 inhibitors were collected from published literatures [2,3,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. The activities of these inhibitors were expressed as IC 50 values for CDK9 inhibition, which range from 2 to 30,000 nM.…”

Section: The Data Setmentioning

confidence: 99%

Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors

Fang

Xiao

Guo

2011

Journal of Molecular Graphics and Modelling

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“…They interact with hydrophobic interaction and make H-bonds with Kinase, especially with a backbone of Glu 81 and Leu83. These compounds have shown promising activity IC50 of 7 μmols [28]. Substituted Indoles [29] and benzopyrans (chromenes) [30] have shown good anticancer activity.…”

Section: Introductionmentioning

confidence: 99%

MOLECULAR DOCKING STUDY ON 1H-(3,4d) PYRAZOLO-PYRIMIDINES AS CYCLIN DEPENDANT KINASE (CDK2) INHIBITORS

Phoujdar

Aland

2016

Int J Curr Pharm Sci

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Objective: CDK2 inhibitors are implicated in several carcinomas viz. Carcinoma of lung, bladder, sarcomas and retinoblastoma. Pyrazolopyrimidines, being purine bioisosters inhibit more than one type of kinase. In this study, we are studying some novel derivatives of 1H-pyrazolo [3,4d] pyrimidines not reported earlier. The objective of the present study is an attempt towards design and development of 1H-[3,4-] pyrazolo-pyrimidines as CDK2 inhibitors through rational drug design. Methods:The present study has been done on CDK2 structure, PDB ID, 3WBL, co-crystallized with ligand PDY from RCSB protein data bank. A series of seventeen 1H-Pyrazolo [3,4-d] pyrimidines feasible for synthesis was docked on the said CDK2 receptor using Auto Dock 4 version, 1.5.6. Outputs were exported to discovery studio 3.5 client for visual inspection of the binding modes and interactions of the compounds with amino acid residues in the active sites. Results:The results of docking studies revealed that the present series of 1H-Pyrazolo [3,4-d] pyrimidines is showing significant binding through hydrogen bonding, hydrophobic, pi and Van der waals interactions, similar to the ligand PDY. Some conserved H-bond interactions comparable to bioisosters and compounds presently under human trials were noted. Ki values predicted in silico also suggest that the series will show promising CDK2 inhibitory activity. Conclusion:The series designed and docked can be further developed by synthesis and in vitro and in vivo activity. The receptor inhibitory activity can also be checked by specific receptor assays.

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Pyrazolo[1,5-a]-1,3,5-triazine as a Purine Bioisostere: Access to Potent Cyclin-Dependent Kinase Inhibitor (R)-Roscovitine Analogue

Cited by 65 publications

References 41 publications

CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells

CDK/CK1 inhibitors roscovitine and CR8 downregulate amplified MYCN in neuroblastoma cells

Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors

MOLECULAR DOCKING STUDY ON 1H-(3,4d) PYRAZOLO-PYRIMIDINES AS CYCLIN DEPENDANT KINASE (CDK2) INHIBITORS

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