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

被引：28

作者：

Murphy, Jennifer M. ^{[1
,2
]}

Armijo, Amanda L. ^{[1
,2
]}

Nomme, Julian ^{[6
]}

Lee, Chi Hang ^{[1
,2
]}

Smith, Quentin A. ^{[3
]}

Li, Zheng ^{[1
,2
]}

Campbell, Dean O. ^{[1
,2
,5
]}

Liao, Hsiang-I ^{[1
,2
]}

Nathanson, David A. ^{[1
,2
]}

Austin, Wayne R. ^{[1
,2
]}

Lee, Jason T. ^{[1
,2
]}

Darvish, Ryan ^{[1
,2
]}

Wei, Liu ^{[1
,2
]}

Wang, Jue ^{[1
,2
]}

Su, Ying ^{[6
]}

Damoiseaux, Robert ^{[4
]}

Sadeghi, Saman ^{[1
,2
]}

Phelps, Michael E. ^{[1
]}

Herschman, Harvey R. ^{[1
,5
]}

Czernin, Johannes ^{[1
,2
]}

Alexandrova, Anastassia N. ^{[3
]}

Jung, Michael E. ^{[3
]}

Lavie, Arnon ^{[6
]}

Radu, Caius G. ^{[1
,2
]}

机构：

[1] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Ahmanson Translat Imaging Div, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Calif NanoSyst Inst, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA

[6] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 17期

基金：

美国国家卫生研究院;

关键词：

NUCLEOSIDE ANALOGS; DRUG DISCOVERY; METABOLISM; SPECIFICITY; ANTICANCER; ACTIVATION; FLUORINE; ENZYME;

D O I：

10.1021/jm400457y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 F-18-L-1-(2'-deoxy-2':-FluoroArabinofuranosyl) Cytosine (F-18-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 = similar to 1-12 nM) using the F-18-L-FAC PET pharmacodynatnic assay identified compounds demonstrating superior in vivo efficacy.

引用

页码：6696 / 6708

页数：13

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