Identification of 6-Aryl-7-Deazapurine Ribonucleoside Phosphonates as Inhibitors of Ecto-5′-Nucleotidase (CD73)

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00216208:11110/25:10501408 RIV/00216208:11310/25:10501408

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Identification of 6-Aryl-7-Deazapurine Ribonucleoside Phosphonates as Inhibitors of Ecto-5′-Nucleotidase (CD73)

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Identification of 6-Aryl-7-Deazapurine Ribonucleoside Phosphonates as Inhibitors of Ecto-5′-Nucleotidase (CD73)

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ACS Pharmacology & Translational Science

ISSN

2575-9108

e-ISSN

2575-9108

Svazek periodika

8

Číslo periodika v rámci svazku

8

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

2575-2585

Kód UT WoS článku

001531635100001

EID výsledku v databázi Scopus

2-s2.0-105013518397