Article

A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration.

Dept of Oncology, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, England.
Journal of Medicinal Chemistry (Impact Factor: 5.48). 11/2010; 53(24):8508-22. DOI: 10.1021/jm100732t
Source: PubMed

ABSTRACT Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC₅₀= 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G₂/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI₅₀= 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.

0 Bookmarks
 · 
107 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cyclin-dependent kinase 5 (CDK5) and Casein kinase 1 (CK1) are both involved in the hyperphosphorylation of the Tau protein and in the amyloid-β production, the two major hallmarks of Alzheimer’s disease. In the present paper, we describe the synthesis and biological evaluation of new series of 2,6,9-trisubstituted purines derived from DRF53, a dual specificity inhibitor of the kinase activity of CDK5 (IC50 = 80 nM) and CK1 (IC50 = 10 nM), and are able to prevent in a dose-dependent manner the CK1-dependent production of amyloid-β in a cell model. Several molecules (e.g., 6e, 6g, 7c) displayed potent kinase inhibitory activities against CDK5 and CK1 (IC50 values ranging from 20 to 50 nM) among which a selective inhibitor of CK1 has been identified (5a, IC50 = 60 nM). In addition, some compounds exhibit sub-micromolar activities against DYRK1A (dual specificity, tyrosine phosphorylation regulated kinase 1A), a kinase involved in Down syndrome and Alzheimer’s disease (6g, IC50 = 510 nM).
    Medicinal Chemistry Research 22(7). · 1.61 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Regioselectivity was examined of reactions between nine 3(5)-aminopyrazoles and 2-acetylcyclopentanone and 2-acetylcyclohexanone under various conditions. A series of cyclopenta[e]pyrazolo-[1,5-a]pyrimidines was obtained. The highest regioselectivity of the reaction was observed in alcohol at 20°C in the presence of a catalytic quantity of trifl uoroacetic acid. The regiostructure of compounds was established by 1H and 13C NMR spectroscopy.
    Russian Journal of Organic Chemistry 08/2012; 48(8). · 0.68 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background:Cyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy.Methods:We generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy.Results:We identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å(2)) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively.Conclusion:We identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer.British Journal of Cancer advance online publication, 26 September 2013; doi:10.1038/bjc.2013.584 www.bjcancer.com.
    British Journal of Cancer 09/2013; · 5.08 Impact Factor