Journal Article

PUBDB-2025-04140

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Acyclic purine and pyrimidine nucleotide analogs as ecto-5′-nucleotidase (CD73) inhibitors

Federico, S. (Corresponding author) ; Renn, C. ; Brehova, P. ; Janeba, Z. ; Moschütz, S. ; Sylvester, K. ; Shamleh, R. A. ; Baburi, H. ; Zimmermann, H. ; El-Tayeb, A. ; Sträter, N. ; Müller, C. E. (Corresponding author)

2025
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.ejmech.2025.117653  doi:10.3204/PUBDB-2025-04140

Abstract: Ecto-5′-nucleotidase (CD73) is a novel target in cancer (immuno)therapy. Its blockade prevents the formation of immunosuppressive and cancer-promoting adenosine from AMP. Here, we report on the development of a series of small molecules that mimic adenine nucleotides, in which the ribose moiety was replaced by an alkyl chain. Its length was found to be crucial for potency. A crystal structure of the N6-disubstituted acyclic ADP analog 26 (N6-benzyl,N6-methyladenine-9-yl)pentyloxydiphosphonate) in complex with human CD73 revealed that the flexible pentyl linker adopts to interdomain rotation angles differing by up to 18.5°. The most potent CD73 inhibitor of the present series was analog 27 (N6-benzyl,N6-methyladenine-9-yl)hexyloxydiphosphonate, PSB-24000) which exhibited submicromolar potency at human CD73 (Ki 563 nM at soluble CD73; Ki 481 nM at membrane-bound CD73 of triple-negative breast cancer cells). Acyclic nucleotide analogs may be advantageous compared to the previously reported nucleotidic CD73 inhibitors due to their high chemical stability, and because less off-target effects are to be expected. The structure-activity relationships discovered in this study provide valuable insights which will be useful for the development of CD73 inhibitors as immunotherapeutic drugs.

Note: C.E.M. is grateful for support by the Deutsche Forschungsgemeinschaft (SFB 1328, project ID 335447717)

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project G:(GEPRIS)335447717 - SFB 1328: Adeninnukleotide in Immunität und Entzündung (335447717) (335447717)

Experiment(s):

1. PETRA Beamline P13 (PETRA III)
2. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2025

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