Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 3, Pages 655-663Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm801340z
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Funding
- EEC
- Canceropole Grand-Ouest
- Institut National du Cancer (INCa)
- Cancer Detection d'Innovations 2006
- Ligue Nationale contre le Cancer
- U.S. NIH [PO1-CA74175]
- Ministere de la Recherche
- Association pour la Recherche sur le Cancer
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Pharmacological inhibitors of cyclin-dependent kinases (CDKs) have a wide therapeutic potential. Among the CDK inhibitors currently under clinical trials, the 2,6,9-trisubstituted purine (R)-roscovitine displays rather high selectivity, low toxicity, and promising antitumor activity. In an effort to improve this structure, we synthesized several bioisosteres of roscovitine. Surprisingly, one of them, pyrazolo[1,5-a]-1,3,5-triazine 7a (N-&-N1, GP0210), displayed significantly higher potency, compared to (R)-roscovitine and imidazo[2,1-f]-1,2,4-triazine 13 (N-&-N2, GP0212), at inhibiting various CDKs and at inducing cell death in a wide variety of human tumor cell lines. This approach may thus provide second generation analogues with enhanced biomedical potential.
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