Development of new deoxycytidine kinase inhibitors and noninvasive in vivo evaluation using positron emission tomography.
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.
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.
Jennifer M
JM
Murphy
Amanda L
AL
Armijo
Julian
J
Nomme
Chi Hang
CH
Lee
Quentin A
QA
Smith
Zheng
Z
Li
Dean O
DO
Campbell
Hsiang-I
HI
Liao
David A
DA
Nathanson
Wayne R
WR
Austin
Jason T
JT
Lee
Ryan
R
Darvish
Liu
L
Wei
Jue
J
Wang
Ying
Y
Su
Robert
R
Damoiseaux
Saman
S
Sadeghi
Michael E
ME
Phelps
Harvey R
HR
Herschman
Johannes
J
Czernin
Anastassia N
AN
Alexandrova
Michael E
ME
Jung
Arnon
A
Lavie
Caius G
CG
Radu
D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003842:Deoxycytidine Kinase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009010:Monte Carlo Method; D049268:Positron-Emission Tomography / Q000379:methods*; D021241:Spectrometry, Mass, Electrospray Ionization
D004791:Enzyme Inhibitors; D003842:Deoxycytidine Kinase