title: Anti-angiogenic effects of purine inhibitors of cyclin dependent kinases.
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.
authors.affiliation: Department of Pharmacy, Center for Drug Research, Ludwig Maximilians University, Munich, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Liebl
authors.forename: Vladimir
authors.initials: V
authors.lastname: Krystof
authors.forename: György
authors.initials: G
authors.lastname: Vereb
authors.forename: Lili
authors.initials: L
authors.lastname: Takács
authors.forename: Miroslav
authors.initials: M
authors.lastname: Strnad
authors.forename: Paul
authors.initials: P
authors.lastname: Pechan
authors.forename: Libor
authors.initials: L
authors.lastname: Havlicek
authors.forename: Marek
authors.initials: M
authors.lastname: Zatloukal
authors.forename: Robert
authors.initials: R
authors.lastname: Fürst
authors.forename: Angelika M
authors.initials: AM
authors.lastname: Vollmar
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahler
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D016510:Corneal Neovascularization / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009924:Organ Culture Techniques; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology*; D000077546:Roscovitine; D013237:Stereoisomerism
chemical_list: D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D018844:Cyclin-Dependent Kinases