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

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

  • J Med Chem. 2013 Sep 12;56(17):6696-708. doi: 10.1021/jm400457y.
Jennifer M Murphy 1,  Amanda L Armijo,  Julian Nomme,  Chi Hang Lee,  Quentin A Smith,  Zheng Li,  Dean O Campbell,  Hsiang-I Liao,  David A Nathanson,  Wayne R Austin,  Jason T Lee,  Ryan Darvish,  Liu Wei,  Jue Wang,  Ying Su,  Robert Damoiseaux,  Saman Sadeghi,  Michael E Phelps,  Harvey R Herschman,  Johannes Czernin,  Anastassia N Alexandrova,  Michael E Jung,  Arnon Lavie,  Caius G Radu
Affiliations

Affiliation

  • 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.
PMID: 23947754 DOI: 10.1021/jm400457y
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.

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