Small-Molecule Allosteric Inhibitors of Human Aspartate Transcarbamoylase Suppress Proliferation of Bone Osteosarcoma Epithelial Cells
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15640%2F24%3A73625189" target="_blank" >RIV/61989592:15640/24:73625189 - isvavai.cz</a>
Result on the web
<a href="https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202300688" target="_blank" >https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202300688</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1002/cmdc.202300688" target="_blank" >10.1002/cmdc.202300688</a>
Alternative languages
Result language
angličtina
Original language name
Small-Molecule Allosteric Inhibitors of Human Aspartate Transcarbamoylase Suppress Proliferation of Bone Osteosarcoma Epithelial Cells
Original language description
Aspartate transcarbamoylase (ATC) is the first committed step in de novo pyrimidine biosynthesis in eukaryotes and plants. A potent transition state analog of human ATCase (PALA) has previously been assessed in clinical trials for the treatment of cancer, but was ultimately unsuccessful. Additionally, inhibition of this pathway has been proposed to be a target to suppress cell proliferation in E. coli, the malarial parasite and tuberculosis. In this manuscript we screened a 70-member library of ATC inhibitors developed against the malarial and tubercular ATCases for inhibitors of the human ATC. Four compounds showed low nanomolar inhibition (IC50 30-120 nM) in an in vitro activity assay. These compounds significantly outperform PALA, which has a triphasic inhibition response under identical conditions, in which significant activity remains at PALA concentrations above 10 mu M. Evidence for a druggable allosteric pocket in human ATC is provided by both in vitro enzyme kinetic, homology modeling and in silico docking. These compounds also suppress the proliferation of U2OS osteoblastoma cells by promoting cell cycle arrest in G0/G1 phase. This report provides the first evidence for an allosteric pocket in human ATC, which greatly enhances its druggability and demonstrates the potential of this series in cancer therapy.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10401 - Organic chemistry
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
ChemMedChem
ISSN
1860-7179
e-ISSN
1860-7187
Volume of the periodical
19
Issue of the periodical within the volume
13
Country of publishing house
DE - GERMANY
Number of pages
7
Pages from-to
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UT code for WoS article
001228695700001
EID of the result in the Scopus database
2-s2.0-85193727434