Discovery of small molecule inhibitors of human uridine-cytidine kinase 2 by high-throughput screening |
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| Affiliation: | 1. Department of Chemistry, Stanford University, Stanford, CA 94305, USA;2. Stanford ChEM-H, Stanford, CA 94305, USA;3. Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA;4. Facilitated Access to Screening Technologies (FAST) Laboratory, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA;5. Department of Genetics, Stanford University, Stanford, CA 94305, USA;1. Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India;2. Institute of Science, Nirma University, Ahmedabad 382481, Gujarat, India;1. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark;2. Interdisciplinary Centre for Clinical Research, University of Erlangen-Nuremberg, Erlangen, Germany;1. Childhood Cancer Research Unit, Department of Women''s and Children''s Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden;2. Theme of Children''s and Women''s Health, Astrid Lindgren Children''s Hospital, Karolinska University Hospital, Stockholm, Sweden;3. Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden;4. Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany;1. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA;2. Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, 01605, USA;3. Broad Institute of Harvard and MIT, 75 Ames Street, Cambridge, MA, 02142, USA;4. Massachusetts Consortium on Pathogen Readiness, Boston, MA, 02115, USA;5. Department of Pathology, University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA;6. Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA;7. National Emerging Infectious Diseases Laboratories, Boston University, Boston, MA, 02118, USA;8. PTC Therapeutics, Inc. South Plainfield, NJ, 07080, USA;9. United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, 21702, USA;10. Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, 01605, USA |
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| Abstract: | Clinically relevant inhibitors of dihydroorotate dehydrogenase (DHODH), a rate-limiting enzyme in mammalian de novo pyrimidine synthesis, have strong antiviral and anticancer activity in vitro. However, they are ineffective in vivo due to efficient uridine salvage by infected or rapidly dividing cells. The pyrimidine salvage enzyme uridine-cytidine kinase 2 (UCK2), a ∼29 kDa protein that forms a tetramer in its active state, is necessary for uridine salvage. Notwithstanding the pharmacological potential of this target, no medicinally tractable inhibitors of the human enzyme have been reported to date. We therefore established and miniaturized an in vitro assay for UCK2 activity and undertook a high-throughput screen against a ∼40,000-compound library to generate drug-like leads. The structures, activities, and modes of inhibition of the most promising hits are described. Notably, our screen yielded non-competitive UCK2 inhibitors which were able to suppress nucleoside salvage in cells both in the presence and absence of DHODH inhibitors. |
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| Keywords: | De novo pyrimidine synthesis Pyrimidine salvage Uridine-cytidine kinase Uridine High-throughput screening Pyrimidine processing inhibitors DHODH inhibitor GSK983 UCK2" },{" #name" :" keyword" ," $" :{" id" :" k0050" }," $$" :[{" #name" :" text" ," _" :" uridine-cytidine kinase 2 DP" },{" #name" :" keyword" ," $" :{" id" :" k0060" }," $$" :[{" #name" :" text" ," _" :" dipyridamole DHODH" },{" #name" :" keyword" ," $" :{" id" :" k0070" }," $$" :[{" #name" :" text" ," _" :" dihydroorotate dehydrogenase CMPK1" },{" #name" :" keyword" ," $" :{" id" :" k0080" }," $$" :[{" #name" :" text" ," _" :" cytidine monophosphate kinase 1 |
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