Discovery of Novel Non-Nucleoside Inhibitors Interacting with Dizinc Ions of CD73.
J Med Chem
; 67(11): 9686-9708, 2024 Jun 13.
Article
em En
| MEDLINE
| ID: mdl-38809692
ABSTRACT
High extracellular concentrations of adenosine triphosphate (ATP) in the tumor microenvironment generate adenosine by sequential dephosphorylation of CD39 and CD73, resulting in potent immunosuppression to inhibit T cell and natural killer (NK) cell function. CD73, as the determining enzyme for adenosine production, has been shown to correlate with poor clinical tumor prognosis. Conventional inhibitors as analogues of adenosine 5'-monophosphate (AMP) may have a risk of further metabolism to adenosine analogues. Here, we report a new series of malonic acid non-nucleoside inhibitors coordinating with zinc ions of CD73. Compound 12f was found to be a superior CD73 inhibitor (IC50 = 60 nM) by structural optimization, and its pharmacokinetic properties were investigated. In mouse tumor models, compound 12f showed excellent efficacy and reversal of immunosuppression in combination with chemotherapeutic agents or checkpoint inhibitors, suggesting that it deserves further development as a novel CD73 inhibitor.
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Base de dados:
MEDLINE
Assunto principal:
5'-Nucleotidase
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article