Development of New Deoxycytidine Kinase Inhibitors and Noninvasive in Vivo Evaluation Using Positron Emission Tomography

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• 作者：Jennifer M. Murphy ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6696-6708
• 全文大小：560K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

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鈥揳ctivity relationship study was carried out. Positron Emission Tomography (PET) using ¹⁸F-L-1-(2鈥?deoxy-2鈥?FluoroArabinofuranosyl) Cytosine (¹⁸F-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鈥?2 nM) using the ¹⁸F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy.