Identification of 6-Aryl-7-Deazapurine Ribonucleoside Phosphonates as Inhibitors of Ecto-5′-Nucleotidase (CD73)
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00638025" target="_blank" >RIV/61388963:_____/25:00638025 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11110/25:10501408 RIV/00216208:11310/25:10501408
Result on the web
<a href="https://doi.org/10.1021/acsptsci.5c00180" target="_blank" >https://doi.org/10.1021/acsptsci.5c00180</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acsptsci.5c00180" target="_blank" >10.1021/acsptsci.5c00180</a>
Alternative languages
Result language
angličtina
Original language name
Identification of 6-Aryl-7-Deazapurine Ribonucleoside Phosphonates as Inhibitors of Ecto-5′-Nucleotidase (CD73)
Original language description
CD73 is a crucial regulator of adenosine production in the tumor microenvironment and, therefore, represents a valuable target for cancer immunotherapy. While different inhibitors of CD73 have been studied, the progress remains hindered by a lack of high-throughput assays that would allow the screening of large chemical libraries. Establishing a sensitive assay for the detection of CD73 activity could enable additions to the CD73 inhibitor chemical space as well as help facilitate a better understanding of the CD73 reaction mechanism. In this study, we focused on the development and adaptation of DIANA for CD73 high-throughput screening and showed that we can detect enzyme inhibition with high sensitivity. We then used this assay to screen an IOCB library, a proprietary set of chemical compounds with a special focus on nucleotide analogues. We identified several scaffolds that inhibit CD73 and in an SAR study demonstrated fine-tuning of the inhibition properties of monophosphonate analogues. Moreover, using a breast cancer cell line as a model with endogenous CD73 expression, we demonstrated the inhibition of CD73 directly on cells. The establishment of a sensitive assay for the detection of CD73 activity allowed us to develop potent inhibitors of the enzyme with low nanomolar inhibition constants. Our findings further promote the importance of CD73 inhibitors 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
30107 - Medicinal chemistry
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 Pharmacology & Translational Science
ISSN
2575-9108
e-ISSN
2575-9108
Volume of the periodical
8
Issue of the periodical within the volume
8
Country of publishing house
US - UNITED STATES
Number of pages
11
Pages from-to
2575-2585
UT code for WoS article
001531635100001
EID of the result in the Scopus database
2-s2.0-105013518397