Trisubstituted Pyrazolopyrimidines as Novel Angiogenesis Inhibitors

0395043 - ÚEB 2014 RIV US eng J - Journal Article
Weitensteiner, S. - Liebl, J. - Kryštof, Vladimír - Havlíček, Libor - Gucký, Tomáš - Strnad, Miroslav - Fuerst, R. - Vollmar, A. - Zahler, S.
Trisubstituted Pyrazolopyrimidines as Novel Angiogenesis Inhibitors.
PLoS ONE. Roč. 8, č. 1 (2013). ISSN 1932-6203. E-ISSN 1932-6203
R&D Projects: GA ČR GAP305/12/0783
Grant - others:GA MŠk(CZ) ED0007/01/01
Program: ED
Institutional research plan: CEZ:AV0Z50380511
Keywords : CYCLIN-DEPENDENT KINASE-5 * ENDOTHELIAL-CELL MIGRATION * IN-VITRO
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 3.534, year: 2013

Current inhibitors of angiogenesis comprise either therapeutic antibodies (e.g. bevacicumab binding to VEGF-A) or small molecular inhibitors of receptor tyrosin kinases like e.g. sunitinib, which inhibits PDGFR and VEGFR. We have recently identified cyclin-dependent kinase 5 (Cdk5) as novel alternative and pharmacologically accessible target in the context of angiogenesis. In the present work we demonstrate that trisubstituted pyrazolo[4,3-d]pyrimidines constitute a novel class of compounds which potently inhibit angiogenesis. All seven tested compounds inhibited endothelial cell proliferation with IC50 values between 1 and 18 mu M. Interestingly, this seems not to be due to cytotoxicity, since none of them showed acute cytotoxic effects on endothelial cells at a concentration of 10 mu M,. The three most potent compounds (LGR1404, LGR1406 and LGR1407) also inhibited cell migration (by 27, 51 and 31%, resp.), chemotaxis (by 50, 70 and 60% in accumulative distance, resp.), and tube formation (by 25, 60 and 30% of total tube length, resp.) at the non-toxic concentration of 10 mu M. Furthermore, angiogenesis was reduced in vivo in the CAM assay by these three compounds. A kinase selectivity profiling revealed that the compounds prevalently inhibit Cdk2, Cdk5 and Cdk9. The phenotype of the migrating cells (reduced formation of lamellipodia, loss of Rac-1 translocation to the membrane) resembles the previously described effects of silencing of Cdk5 in endothelial cells. We conclude that especially LGR1406 and LGR1407 are highly attractive anti-angiogenic compounds, whose effects seem to largely depend on their Cdk5 inhibiting properties.
Permanent Link: http://hdl.handle.net/11104/0223205