Acyclic purine and pyrimidine nucleotide analogs as ecto-5'-nucleotidase (CD73) inhibitors
Jazyk angličtina Země Francie Médium print-electronic
Typ dokumentu časopisecké články
PubMed
40378575
DOI
10.1016/j.ejmech.2025.117653
PII: S0223-5234(25)00418-0
Knihovny.cz E-zdroje
- Klíčová slova
- Acyclic nucleotides, CD73, Cancer immunotherapy, Ecto-5′-nucleotidase, Inhibitors, Synthesis, X-ray co-crystal structure,
- MeSH
- 5'-nukleotidasa * antagonisté a inhibitory metabolismus MeSH
- cisplatina chemie farmakologie MeSH
- GPI-vázané proteiny antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů * farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- purinové nukleotidy * chemie farmakologie chemická syntéza MeSH
- pyrimidinové nukleotidy * chemie farmakologie chemická syntéza MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 5'-nukleotidasa * MeSH
- cisplatina MeSH
- GPI-vázané proteiny MeSH
- inhibitory enzymů * MeSH
- NT5E protein, human MeSH Prohlížeč
- purinové nukleotidy * MeSH
- pyrimidinové nukleotidy * 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.
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