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Acyclic purine and pyrimidine nucleotide analogs as ecto-5'-nucleotidase (CD73) inhibitors
S. Federico, C. Renn, P. Brehova, Z. Janeba, S. Moschütz, K. Sylvester, RA. Shamleh, H. Baburi, H. Zimmermann, A. El-Tayeb, N. Sträter, CE. Müller
Language English Country France
Document type Journal Article
- MeSH
- 5'-Nucleotidase * antagonists & inhibitors metabolism MeSH
- Cisplatin chemistry pharmacology MeSH
- GPI-Linked Proteins antagonists & inhibitors metabolism MeSH
- Enzyme Inhibitors * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Purine Nucleotides * chemistry pharmacology chemical synthesis MeSH
- Pyrimidine Nucleotides * chemistry pharmacology chemical synthesis MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
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.
References provided by Crossref.org
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