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J Med Chem. 2013 Sep 12;56(17):6696-708. doi: 10.1021/jm400457y. Epub 2013 Aug 15.

Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography.

Author information

1
Department of Molecular and Medical Pharmacology, §Ahmanson Translational Imaging Division, ⊥Department of Chemistry and Biochemistry, #California NanoSystems Institute, △Department of Biological Chemistry, University of California, Los Angeles , 650 Charles E. Young Dr. S., Los Angeles, California 90095, United States.

Abstract

Combined inhibition of ribonucleotide reductase and deoxycytidine kinase (dCK) in multiple cancer cell lines depletes deoxycytidine triphosphate pools leading to DNA replication stress, cell cycle arrest, and apoptosis. Evidence implicating dCK in cancer cell proliferation and survival stimulated our interest in developing small molecule dCK inhibitors. Following a high throughput screen of a diverse chemical library, a structure-activity relationship study was carried out. Positron Emission Tomography (PET) using (18)F-L-1-(2'-deoxy-2'-FluoroArabinofuranosyl) Cytosine ((18)F-L-FAC), a dCK-specific substrate, was used to rapidly rank lead compounds based on their ability to inhibit dCK activity in vivo. Evaluation of a subset of the most potent compounds in cell culture (IC50 = ∼1-12 nM) using the (18)F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy.

PMID:
23947754
PMCID:
PMC3789385
DOI:
10.1021/jm400457y
[Indexed for MEDLINE]
Free PMC Article
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