Discovery of small molecule inhibitors of human uridine-cytidine kinase 2 by high-throughput screening.
DHODH inhibitor
De novo pyrimidine synthesis
GSK983
High-throughput screening
Pyrimidine processing inhibitors
Pyrimidine salvage
Uridine
Uridine-cytidine kinase
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
15 09 2019
15 09 2019
Historique:
received:
18
05
2019
revised:
03
08
2019
accepted:
05
08
2019
pubmed:
20
8
2019
medline:
21
10
2020
entrez:
18
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31420268
pii: S0960-894X(19)30536-0
doi: 10.1016/j.bmcl.2019.08.010
pmc: PMC6719797
mid: NIHMS1537779
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Small Molecule Libraries
0
UCK2 protein, human
EC 2.7.1.48
Uridine Kinase
EC 2.7.1.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
2559-2564Subventions
Organisme : NIAID NIH HHS
ID : U19 AI109662
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
Références
Antiviral Res. 2009 Apr;82(1):1-11
pubmed: 19187793
Eur J Med Chem. 2012 Jan;47(1):18-23
pubmed: 22000923
J Virol. 2011 Jul;85(13):6548-56
pubmed: 21507975
Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):6739-44
pubmed: 21502533
Nat Chem Biol. 2016 May;12(5):361-6
pubmed: 27018887
Mol Pharmacol. 1985 Nov;28(5):454-60
pubmed: 2997596
Bioorg Med Chem. 2018 Jan 15;26(2):309-339
pubmed: 29273417
Trends Pharmacol Sci. 1999 May;20(5):218-25
pubmed: 10354618
Mol Pharmacol. 2001 May;59(5):1181-6
pubmed: 11306702
Structure. 2004 May;12(5):751-64
pubmed: 15130468
J Biol Chem. 1974 Nov 10;249(21):6945-50
pubmed: 4371054
Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15779-84
pubmed: 18840688
Jpn J Cancer Res. 2002 Jul;93(7):825-33
pubmed: 12149149
Cancer Res. 1980 Nov;40(11):3921-7
pubmed: 7471043
Structure. 2000 Jan 15;8(1):25-33
pubmed: 10673429
Bioorg Med Chem Lett. 2019 Jan 15;29(2):225-229
pubmed: 30522954
Bioorg Med Chem. 2013 Sep 15;21(18):5657-68
pubmed: 23932070
J Biol Chem. 2005 Jun 3;280(22):21169-75
pubmed: 15772079
Science. 2017 Mar 17;355(6330):1124-1125
pubmed: 28302808
Antimicrob Agents Chemother. 1987 Oct;31(10):1535-41
pubmed: 3435102
Genomics. 2013 Oct;102(4):250-6
pubmed: 23806289
Eur J Med Chem. 2010 Jun;45(6):2695-9
pubmed: 20231044
J Breast Cancer. 2017 Jun;20(2):132-141
pubmed: 28690649
Bioorg Chem. 2018 Aug;78:312-323
pubmed: 29625271
Curr Opin Biotechnol. 2017 Dec;48:127-134
pubmed: 28458037
Future Med Chem. 2009 May;1(2):303-26
pubmed: 21425971
Bioorg Chem. 2018 Aug;78:358-371
pubmed: 29627656
Bioorg Med Chem Lett. 2017 Jun 1;27(11):2544-2548
pubmed: 28404375
Mol Carcinog. 2009 Apr;48(4):369-78
pubmed: 19117014
PLoS One. 2017 Jan 19;12(1):e0170233
pubmed: 28103302