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Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism

Authors
 Evan R Abt  ;  Ethan W Rosser  ;  Matthew A Durst  ;  Vincent Lok  ;  Soumya Poddar  ;  Thuc M Le  ;  Arthur Cho  ;  Woosuk Kim  ;  Liu Wei  ;  Janet Song  ;  Joseph R Capri  ;  Shili Xu  ;  Nanping Wu  ;  Roger Slavik  ;  Michael E Jung  ;  Robert Damoiseaux  ;  Johannes Czernin  ;  Timothy R Donahue  ;  Arnon Lavie  ;  Caius G Radu 
Citation
 CELL CHEMICAL BIOLOGY, Vol.27(2) : 197-205, 2020-02 
Journal Title
CELL CHEMICAL BIOLOGY
ISSN
 2451-9456 
Issue Date
2020-02
MeSH
Binding Sites ; Cell Line, Tumor ; Cell Survival / drug effects ; Crystallography, X-Ray ; Dihydroorotate Dehydrogenase ; Drug Design ; Equilibrative Nucleoside Transporter 1 / antagonists & inhibitors* ; Equilibrative Nucleoside Transporter 1 / metabolism ; Humans ; Molecular Dynamics Simulation ; Oxidoreductases Acting on CH-CH Group Donors / antagonists & inhibitors* ; Oxidoreductases Acting on CH-CH Group Donors / genetics ; Oxidoreductases Acting on CH-CH Group Donors / metabolism ; Protein Kinase Inhibitors / chemistry* ; Protein Kinase Inhibitors / metabolism ; Protein Kinase Inhibitors / pharmacology ; Pyrimidine Nucleosides / metabolism* ; Small Molecule Libraries / chemistry
Keywords
cancer metabolism ; phenotypic screening ; pyrimidine metabolism ; target identification
Abstract
Biosynthesis of the pyrimidine nucleotide uridine monophosphate (UMP) is essential for cell proliferation and is achieved by the activity of convergent de novo and salvage metabolic pathways. Here we report the development and application of a cell-based metabolic modifier screening platform that leverages the redundancy in pyrimidine metabolism for the discovery of selective UMP biosynthesis modulators. In evaluating a library of protein kinase inhibitors, we identified multiple compounds that possess nucleotide metabolism modifying activity. The JNK inhibitor JNK-IN-8 was found to potently inhibit nucleoside transport and engage ENT1. The PDK1 inhibitor OSU-03012 (also known as AR-12) and the RAF inhibitor TAK-632 were shown to inhibit the therapeutically relevant de novo pathway enzyme DHODH and their affinities were unambiguously confirmed through in vitro assays and co-crystallization with human DHODH.
Files in This Item:
T9992020488.pdf Download
DOI
10.1016/j.chembiol.2019.10.012
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
Yonsei Authors
Cho, Arthur Eung Hyuck(조응혁) ORCID logo https://orcid.org/0000-0001-8670-2473
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/190263
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