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Anti-angiogenic effects of novel cyclin-dependent kinase inhibitors with a pyrazolo[4,3-d]pyrimidine scaffold
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SYSNO ASEP 0463991 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Anti-angiogenic effects of novel cyclin-dependent kinase inhibitors with a pyrazolo[4,3-d]pyrimidine scaffold Tvůrce(i) 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)Zdroj.dok. British Journal of Pharmacology. - : Wiley - ISSN 0007-1188
Roč. 173, č. 17 (2016), s. 2645-2656Poč.str. 12 s. Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova CELL-CYCLE ; PURINE ANALOGS ; CONCISE GUIDE Vědní obor RIV FD - Onkologie a hematologie CEP GA14-19590S GA ČR - Grantová agentura ČR Institucionální podpora UEB-Q - RVO:61389030 UT WOS 000383258400007 DOI 10.1111/bph.13546 Anotace 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.Pracoviště Ústav experimentální botaniky Kontakt David Klier, knihovna@ueb.cas.cz, Tel.: 220 390 469 Rok sběru 2017
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