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Molecular Pharmacology

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Research ArticleArticle

A Novel Roscovitine Derivative Potently Induces G1-Phase Arrest in Platelet-Derived Growth Factor-BB-Activated Vascular Smooth Muscle Cells

Irene M. Sroka, Elke H. Heiss, Libor Havlicek, Frank Totzke, Yasmin Aristei, Paul Pechan, Michael H. G. Kubbutat, Miroslav Strnad and Verena M. Dirsch
Molecular Pharmacology February 2010, 77 (2) 255-261; DOI: https://doi.org/10.1124/mol.109.060327
Irene M. Sroka
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Elke H. Heiss
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Libor Havlicek
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Frank Totzke
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Yasmin Aristei
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Paul Pechan
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Michael H. G. Kubbutat
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Miroslav Strnad
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Verena M. Dirsch
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Abstract

Abnormal vascular smooth muscle cell (VSMC) proliferation contributes to the pathogenesis of restenosis. Thus, drugs interfering with cell cycle progression in VSMC are promising candidates for an antirestenotic therapy. In this study, we pharmacologically characterize N-5-(2-aminocyclohexyl)-N-7-benzyl-3-isopropyl-1(2)H-pyrazolo[4,3-d]pyrimidine-5,7-di-amine (LGR1406), a novel derivative of the cyclin-dependent kinase (CDK) inhibitor roscovitine (ROSC), in PDGF-BB-activated VSMC. Cell proliferation was quantified measuring DNA synthesis via 5-bromo-2′-deoxyuridine incorporation. Analysis of cell cycle distribution was done by flow cytometry using propidium iodide-stained nuclei. Key regulators of the cell cycle and relevant signaling pathways were dissected by Western blot analyses. In addition, in vitro kinase assays and in silico studies regarding the pharmacokinetic profile of both compounds were performed. LGR1406 shows a stronger (IC50 = 3.0 μM) antiproliferative activity than ROSC (IC50 = 16.9 μM), halting VSMCs in G0/G1 phase of the cell cycle, whereas ROSC does not arrest but rather delays cell cycle progression. Neither of the compounds interferes with early PDGF-BB-induced signaling pathways (p38, extracellular signal-regulated kinase 1/2, c-Jun NH2-terminal kinase, Akt, signal transducer and activator of transcription 3), and both inhibit CDKs, with LGR1406 exerting a slightly higher potency against CDK1/2 and 4 than ROSC. Expression of cyclins A and E as well as hyperphosphorylation of the pocket proteins retinoblastoma protein and p107 are negatively affected by both compounds, although to a different extent. In silico calculations predicted a much higher metabolic stability for LGR1406 compared with ROSC. Altogether, ROSC derivatives, such as LGR1406 seem to be promising compounds for further development in antirestenotic therapy.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the European Union within the sixth framework program project “ProKinase Research” [Grant LSHB-CT-2004-503467]; the Czech Grant Agency [Grant 8301/08/1649]; and the Czech Ministry of Education [Grant MSM 6198959216].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.060327

  • ABBREVIATIONS:

    VSMC
    vascular smooth muscle cell
    Ang II
    angiotensin II
    BrdU
    5-bromo-2′-deoxyuridine
    CDK
    cyclin-dependent kinase
    DMSO
    dimethyl sulfoxide
    ERK
    extracellular signal-regulated kinase
    HSA
    human serum albumin
    ISS
    in-stent stenosis
    MAPK
    mitogen-activated protein kinase
    PBS
    phosphate-buffered saline
    PDGF
    platelet-derived growth factor
    Rb
    retinoblastoma protein
    ROSC
    roscovitine
    LGR1406
    N-5-(2-aminocyclohexyl)-N-7-benzyl-3-isopropyl-1(2)H-pyrazolo[4,3-d]pyrimidine-5,7-di-amine
    PI
    propidium iodide
    VD
    volume distribution
    ANOVA
    analysis of variance.

  • Received August 14, 2009.
  • Accepted November 2, 2009.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (2)
Molecular Pharmacology
Vol. 77, Issue 2
1 Feb 2010
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Research ArticleArticle

A Novel Roscovitine Derivative Potently Induces G1-Phase Arrest in Platelet-Derived Growth Factor-BB-Activated Vascular Smooth Muscle Cells

Irene M. Sroka, Elke H. Heiss, Libor Havlicek, Frank Totzke, Yasmin Aristei, Paul Pechan, Michael H. G. Kubbutat, Miroslav Strnad and Verena M. Dirsch
Molecular Pharmacology February 1, 2010, 77 (2) 255-261; DOI: https://doi.org/10.1124/mol.109.060327

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Research ArticleArticle

A Novel Roscovitine Derivative Potently Induces G1-Phase Arrest in Platelet-Derived Growth Factor-BB-Activated Vascular Smooth Muscle Cells

Irene M. Sroka, Elke H. Heiss, Libor Havlicek, Frank Totzke, Yasmin Aristei, Paul Pechan, Michael H. G. Kubbutat, Miroslav Strnad and Verena M. Dirsch
Molecular Pharmacology February 1, 2010, 77 (2) 255-261; DOI: https://doi.org/10.1124/mol.109.060327
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