2. Academic Validation
  3. CD73 inhibition by purine cytotoxic nucleoside analogue-based diphosphonates

CD73 inhibition by purine cytotoxic nucleoside analogue-based diphosphonates

  • Eur J Med Chem. 2018 Sep 5:157:1051-1055. doi: 10.1016/j.ejmech.2018.08.035.
Charles Dumontet 1,  Suzanne Peyrottes 2,  Céline Rabeson 2,  Emeline Cros-Perrial 3,  Pierre Yves Géant 2,  Laurent Chaloin 4,  Lars Petter Jordheim 5
Affiliations

Affiliations

  • 1 Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France; Hospices Civils de Lyon, Lyon, France.
  • 2 Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Univ. de Montpellier, ENSCM, Campus Triolet, cc1705, Place Eugène Bataillon, 34095, Montpellier, France.
  • 3 Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France.
  • 4 Institut de Recherche en Infectiologie de Montpellier (IRIM), Univ. de Montpellier, CNRS, Montpellier, France.
  • 5 Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, 69008, France. Electronic address: lars-petter.jordheim@univ-lyon1.fr.
PMID: 30176535 DOI: 10.1016/j.ejmech.2018.08.035
Abstract

The ecto-5'-nucleotidase CD73 has emerged as an important drug target in oncoimmunology as well as in Other Diseases. We describe new ADP analogues as CD73 inhibitors based on the replacement of the adenosine moiety, in the reference inhibitor APCP, by purine nucleoside analogues. Compounds were assessed for CD73 inhibition both on purified recombinant protein and on CD73-expressing Cancer cells. The clofarabine-containing compound (2) was shown to be more potent than APCP with IC50 values of 0.18 μM (vs. 3.8 μM) on purified protein and 0.24 μM (vs. 23.6 μM) on CD73 expressed on cells. This work gives additional insights into structure-activity relationship of substrate-analogues as CD73 inhibitors.

Keywords

CD73; Cancer; Enzyme inhibitor; Immunology; Nucleotide.

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