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Anti-angiogenic effects of purine inhibitors of cyclin dependent kinases

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Abstract

Small molecular inhibitors of Cyclin dependent kinases (Cdks) are currently being developed as anticancer therapeutics due to their antiproliferative properties. The purine Cdk specific inhibitor (R)-roscovitine (seliciclib, CYC202) represents one of the most promising of these compounds. It is currently evaluated in clinical trials concerning cancer therapy. Recently, we have shown that roscovitine exerts potent antiangiogenic effects and elucidated Cdk5 as a new player in angiogenesis. These findings introduce Cdk5 as novel target for antiangiogenic therapy, and Cdk5 inhibitors as an attractive therapeutic approach. Here, we present the antiangiogenic profile of 15 derivatives of roscovitine in vitro and in vivo and provide structure activity relationships of the roscovitine analogs. The (S)-isomer LGR561 and the respective (R)- and (S)-isomers LGR848 and LGR849 strongly inhibited proliferation and cell cycle progression, induced cell death, and reduced migration of endothelial cells in vitro. In comparison to roscovitine, these compounds showed an increased potency to inhibit Cdk2, Cdk5, Cdk7, and Cdk9. By analyzing the effects of LGR561, LGR848, and LGR849 on endothelial cell tube formation, mouse aortic ring sprouting, angiogenesis in the chick chorioallantoic membrane, and neovessel formation in the mouse cornea, we elucidate the two (S)-isomers LGR561 and LGR849 as highly potent inhibitors of angiogenesis. This study provides first information on how to modify roscovitine to develop Cdk inhibitors with increased antiangiogenic activity and suggests the application of existing and the development of new Cdk inhibitors to inhibit both, cancer cell proliferation and angiogenesis.

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Acknowledgments

We thank C. Niemann, H. Stöcker, J. Peliskova, and S. Schnegg for their help with the in vitro models. We thank ProQinase (Freiburg, Germany) for performing in vitro Cdk activity assays. The EU-project PROKINASE No 503467 is gratefully acknowledged. M. Strnad and V. Krystof were supported by projects MSM6198959216 and GACR204/08/0511.

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Authors and Affiliations

  1. Department of Pharmacy, Center for Drug Research, Ludwig Maximilians University, Butenandtstr. 5-13, 81377, Munich, Germany

    Johanna Liebl, Robert Fürst, Angelika M. Vollmar & Stefan Zahler

  2. Laboratory of Growth Regulators, Faculty of Science, Palacky University and Institute of Experimental Botany AS CR, 78371, Olomouc, Czech Republic

    Vladimir Krystof, Miroslav Strnad, Libor Havlicek & Marek Zatloukal

  3. Medical and Health Science Centre, Department of Biophysics and Cell Biology, University of Debrecen, 4032, Debrecen, Hungary

    György Vereb

  4. Medical and Health Science Centre, Department of Ophthalmology, University of Debrecen, 4032, Debrecen, Hungary

    Lili Takács

  5. C3 Bio GmbH, 82008, Unterhaching, Germany

    Paul Pechan

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  1. Johanna Liebl
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  2. Vladimir Krystof
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  3. György Vereb
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  10. Angelika M. Vollmar
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  11. Stefan Zahler
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Correspondence to Stefan Zahler.

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Liebl, J., Krystof, V., Vereb, G. et al. Anti-angiogenic effects of purine inhibitors of cyclin dependent kinases. Angiogenesis 14, 281–291 (2011). https://doi.org/10.1007/s10456-011-9212-6

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  • DOI: https://doi.org/10.1007/s10456-011-9212-6

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