Discovery and Structural Optimization of 2-Hydrazinopyrimidin-4-one Analogs Inhibiting Human ADP-Ribosylhydrolase ARH3
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F25%3A00640525" target="_blank" >RIV/68378050:_____/25:00640525 - isvavai.cz</a>
Result on the web
<a href="https://doi.org/10.1021/acschembio.5c00461" target="_blank" >https://doi.org/10.1021/acschembio.5c00461</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acschembio.5c00461" target="_blank" >10.1021/acschembio.5c00461</a>
Alternative languages
Result language
angličtina
Original language name
Discovery and Structural Optimization of 2-Hydrazinopyrimidin-4-one Analogs Inhibiting Human ADP-Ribosylhydrolase ARH3
Original language description
Poly-ADP-ribosylation at sites of DNA damage, catalyzed by PARP enzymes, activates the DNA damage response, chromatin remodeling, and DNA repair. The modification is reversed by two enzymes in humans: PARG, which efficiently hydrolyzes the poly-ADP-ribose chains, and ARH3, which is the key enzyme for removing the last proximal mono-ADP-ribose from serine residues. While inhibitor development has largely focused on PARPs and PARG, no potent and selective inhibitors for ARH3 are currently available. We optimized a FRET-based competition assay for ARH3 and carried out high-throughput screening of small-molecule inhibitors. One hit compound, 1, with a potency of 22 mu M was discovered, and through structure-activity relationship studies and synthesis, we improved its potency 10-fold to 2 mu M (compound 27, MDOLL-0286). We demonstrate that the compound inhibits ARH3's poly-ADP-ribose hydrolytic activity on cellular substrates. Intriguingly, it does not effectively inhibit the hydrolysis of mono-ADP-ribosylation from natural protein substrates. This is despite the fact that the cocrystal structure of compound 1 bound to ARH3 reveals its overlap with the enzyme's ADP-ribose binding site, agreeing with the competition in the FRET assay. The first experimental ARH3 inhibitor complex provides a valuable starting point for developing more potent chemical probes to study DNA damage response mechanisms in the future.
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
10608 - Biochemistry and molecular biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
ACS Chemical Biology
ISSN
1554-8929
e-ISSN
1554-8937
Volume of the periodical
20
Issue of the periodical within the volume
10
Country of publishing house
US - UNITED STATES
Number of pages
13
Pages from-to
2438-2450
UT code for WoS article
001571594200001
EID of the result in the Scopus database
2-s2.0-105018931207