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Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography. 2013
Jennifer M Murphy, and
Amanda L Armijo, and
Julian Nomme, and
Chi Hang Lee, and
Quentin A Smith, and
Zheng Li, and
Dean O Campbell, and
Hsiang-I Liao, and
David A Nathanson, and
Wayne R Austin, and
Jason T Lee, and
Ryan Darvish, and
Liu Wei, and
Jue Wang, and
Ying Su, and
Robert Damoiseaux, and
Saman Sadeghi, and
Michael E Phelps, and
Harvey R Herschman, and
Johannes Czernin, and
Anastassia N Alexandrova, and
Michael E Jung, and
Arnon Lavie, and
Caius G Radu
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.
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.
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Dean O Campbell, and
Hsiang-I Liao, and
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Michael E Phelps, and
Harvey R Herschman, and
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Jason T Lee, and
Ryan Darvish, and
Liu Wei, and
Jue Wang, and
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Robert Damoiseaux, and
Saman Sadeghi, and
Michael E Phelps, and
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