Nucleotide-Derived Competitive Inhibitors of Ectonucleotidase CD39─A Promising Extracellular Target for Immunotherapy of Cancer

  • J Med Chem. 2026 May 14;69(9):10828-10864. doi: 10.1021/acs.jmedchem.6c00054.
Chunyang Bi  1 ,  Florian Schwermer  1 ,  Laura Schäkel  1 ,  Salahuddin Mirza  1 ,  Helay Baburi  1 ,  Patrick Riziki  1 ,  Constanze C Schmies  1 ,  Riekje Winzer  2 ,  Riham Idris  1 ,  Georg Rolshoven  1 ,  Julia Schilling  1 ,  Leon Luckenbach  1 ,  Julie Pelletier  3 ,  Luca Svolacchia Brusoni  1 ,  Haneen Al Hroub  1 ,  Ghazl Al Hamwi  1 ,  Vittoria Lopez  1 ,  Areso Ahmadsay  1 ,  Luca Raulien  1 ,  Katharina Sylvester  1 ,  Jean Sévigny  3  4 ,  Eva Tolosa  2 ,  Andreas H Guse  5 ,  Christa E Müller  1
Affiliations
  • 1. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Sciences Bonn (PSB), Pharmaceutical & Medicinal Chemistry, University of Bonn, 53121 Bonn, Germany.
  • 2. Department of Immunology, Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 3. Axe Maladies Infectieuses et Immunitaires, Centre de Recherche du CHU de Québec - Université Laval, Québec City, Quebec G1V 4G2, Canada.
  • 4. Départment de Microbiologie-Infectiologie et d'Immunologie, Centres PROTEO-ULaval et ARThrite, Faculté de Médecine, Université Laval, Quebec City, Quebec G1V 0A6, Canada.
  • 5. The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
PMID: 42067197 DOI: 10.1021/acs.jmedchem.6c00054
Abstract

Ectonucleotidases catalyze the hydrolysis of extracellular nucleotides, maintaining the balance between proinflammatory ATP and immunosuppressive adenosine. In the present study, we developed potent competitive inhibitors of the main ATP-hydrolyzing ectoenzyme nucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39) based on 8-butylthio-AMP as a lead structure. Altogether, 88 purine nucleotides and analogs with broad structural modifications were synthesized, 78 of which are new compounds. 8-Substitution of the purine scaffold with bulky residues is essential for high potency and confers metabolic stability. 8-(1-Naphthylthio)-N6-(4-phenylbutyl)-AMP (42b, PSB-24379) is the most potent CD39 inhibitor of the series (Ki 77.4 nM), showing ancillary CD73 inhibition (Ki 240 nM). Docking into a human CD39 homology model rationalized key interactions. PSB-24379 reduced ATP hydrolysis in melanoma and breast Cancer cell membranes and partially reverted ATP-mediated effects on T cell activation and proliferation in an ATP-rich environment. These CD39 inhibitors represent high-quality tool compounds with potential as drugs for immunotherapy of Cancer.

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