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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

DOI: 10.1021/jm100732t DOI Help
PMID: 21080703 PMID Help

Authors: Dean A. Heathcote (Imperial College London) , Hetal Patel (Imperial College London) , Sebastian H. B. Kroll (Imperial College London) , Pascale Hazel (Imperial College London) , Manikandan Periyasamy (Imperial College London) , Mary Alikian (Imperial College London) , Seshu K. Kanneganti (Imperial College London) , Ashutosh S. Jogalekar (Emory University) , Bodo Scheiper (Imperial College London) , Marion Barbazanges (Imperial College London) , Andreas Blum (Imperial College London) , Jan Brackow (Imperial College London) , Alekasandra Siwicka (Imperial College London) , Robert D. M. Pace (Imperial College London) , Matthew J. Fuchter (Imperial College London) , James P. Snyder (Emory University) , Dennis C. Liotta (Emory University) , Paul. S. Freemont (Imperial College London) , Eric O. Aboagye (Imperial College London) , R. Charles Coombes (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 53 (24) , PAGES 8508 - 8522

State: Published (Approved)
Published: November 2010

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.

Journal Keywords: Oral; Animals; Antineoplastic; Biological; Blood; Cell; Cell; Tumor; Cell; Crystallography; X-Ray; Cyclin-Dependent; Cyclin-Dependent; Female; Humans; In; Mice; Mice; Nude; Microsomes; Liver; Models; Molecular; Phosphorylation; Protein; Pyrazoles; Pyrimidines; Stereoisomerism; Structure-Activity; Xenograft Model Antitumor Assays

Subject Areas: Chemistry


Instruments: I02-Macromolecular Crystallography

Added On: 25/09/2015 10:27

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