Evidence map›Paper›PMID 31420268›Full record

ArticleBioorganic & medicinal chemistry letters2019

Discovery of small molecule inhibitors of human uridine-cytidine kinase 2 by high-throughput screening.

Ayse Okesli-Armlovich, Amita Gupta, Marta Jimenez, Douglas Auld, Qi Liu, Michael C Bassik, Chaitan Khosla

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Bioorganic & medicinal chemistry letters, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
0.9field-weighted citation impact, top 25% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed, 18 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 2 institutions in 1 country.

Ayse Okesli-ArmlovichDepartment of Chemistry, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford, CA 94305, USA.
Amita GuptaStanford ChEM-H, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
Marta JimenezFacilitated Access to Screening Technologies (FAST) Laboratory, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Douglas AuldFacilitated Access to Screening Technologies (FAST) Laboratory, Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
Qi LiuDepartment of Chemistry, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford, CA 94305, USA.
Michael C BassikStanford ChEM-H, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Chaitan KhoslaDepartment of Chemistry, Stanford University, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA. Electronic address: khosla@stanford.edu.
Stanford University · USAccess to Wholistic and Productive Living Institute · US

Funding

Translational Incubator CoreU19AI109662 · NIAID · STANFORD UNIVERSITY · PI GLENN, JEFFREY S · 2014 to 2019
$28.6M
NIAID NIH HHS U19 AI109662
6 · The paper itself

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.

Indexed as

Drug DiscoveryHigh-Throughput Screening AssaysDose-Response Relationship, DrugEnzyme InhibitorsHumansMolecular StructureSmall Molecule LibrariesStructure-Activity RelationshipUridine KinaseEnzyme InhibitorsSmall Molecule LibrariesUCK2 protein, humanUridine KinaseDe novo pyrimidine synthesisDHODH inhibitorGSK983High-throughput screeningPyrimidine processing inhibitorsPyrimidine salvageUridineUridine-cytidine kinase

Identifiers

PMID31420268
PMCPMC6719797
OpenAlexW2964629852

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.