Number of the records: 1
Anti-angiogenic effects of novel cyclin-dependent kinase inhibitors with a pyrazolo[4,3-d]pyrimidine scaffold
- 1.
SYSNO ASEP 0463991 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Anti-angiogenic effects of novel cyclin-dependent kinase inhibitors with a pyrazolo[4,3-d]pyrimidine scaffold Author(s) Zhang, S. (DK)
Ulrich, M. (DE)
Gromnicka, A. (DE)
Havlíček, Libor (UEB-Q) RID, ORCID
Kryštof, Vladimír (UEB-Q) RID, ORCID
Jorda, Radek (UEB-Q) ORCID, RID
Strnad, Miroslav (UEB-Q) RID, ORCID
Vollmar, A. M. (DE)
Zahler, S. (DE)Source Title British Journal of Pharmacology. - : Wiley - ISSN 0007-1188
Roč. 173, č. 17 (2016), s. 2645-2656Number of pages 12 s. Language eng - English Country GB - United Kingdom Keywords CELL-CYCLE ; PURINE ANALOGS ; CONCISE GUIDE Subject RIV FD - Oncology ; Hematology R&D Projects GA14-19590S GA ČR - Czech Science Foundation (CSF) Institutional support UEB-Q - RVO:61389030 UT WOS 000383258400007 DOI 10.1111/bph.13546 Annotation Cyclin-dependent kinase 5 (CDK5) has recently emerged as an attractive target in several tumour entities. Inhibition of CDK5 has been shown to have anti-angiogenic effects in vitro and in vivo. However, potent inhibitors of CDK5, which can be applied in vivo, are still scarce. We have recently developed a new series of 5-substituted 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines that show a preference for inhibiting CDK5 and tested them in vitro and in vivo in a murine model of hepatocellular carcinoma.
All compounds were initially examined for effects on proliferation of HUVECs. The most potent compounds were then tested on migration, and one of them, LGR2674, was selected for assessing effects on nuclear fragmentation, cell cycle, cell viability and metabolic activity. Furthermore, LGR2674 was tested in a tube formation assay and in vivo in a murine model of hepatocellular carcinoma, induced by s.c. injection of HUH7 cells (measurement of in vivo toxicity, tumour vascularization, tumour cell proliferation and tumour size).
LGR2674 showed an EC50 in the low nanomolar range in the proliferation and migration assays. Cytotoxic effects started at 50 nM, a concentration that did not influence the cell cycle. In vivo, LGR2674 was well tolerated and caused a clear reduction in vessel density in the tumours; also tumour cell proliferation was inhibited and tumour growth retarded.
Pyrazolo[4,3-d]pyrimidine is a novel scaffold for the development of potent CDK inhibitors with in vivo potential. Such structures are good candidates for broadening our pharmacological arsenal against various tumours.Workplace Institute of Experimental Botany Contact David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Year of Publishing 2017
Number of the records: 1