Pyrazolo[1,5-a]-1,3,5-triazine as a purine bioisostere: access to potent cyclin-dependent kinase inhibitor (R)-roscovitine analogue.
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Popowycz F, Fournet G, Schneider C, Bettayeb K, Ferandin Y, Lamigeon C, Tirado OM, Mateo-Lozano S, Notario V, Colas P, Bernard P, Meijer L, Joseph B
Pyrazolo[1,5-a]-1,3,5-triazine as a purine bioisostere: access to potent cyclin-dependent kinase inhibitor (R)-roscovitine analogue.
J Med Chem. 2009 Feb 12;52(3):655-63. doi: 10.1021/jm801340z.
- PubMed ID
- 19128055 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) (2R)-2-{[4-(benzylamino)-8-(1-methylethyl)pyrazolo[1,5-a][1,3,5]triazin-2-yl]amino}butan-1-ol Cyclin-dependent kinase 2 IC 50 (nM) 40 7.5 30 Details Seliciclib Cyclin-dependent kinase 2 IC 50 (nM) 220 7.5 30 Details Seliciclib Cyclin-dependent kinase 7 IC 50 (nM) 800 7.5 30 Details Seliciclib Cyclin-dependent kinase 9 IC 50 (nM) 230 7.5 30 Details