Design, Synthesis, and Antitumor Activity Evaluation of Novel Dual A2A/A2B Adenosine Receptor Antagonists

  • J Med Chem. 2026 Sep 10;69(17):20370-20391. doi: 10.1021/acs.jmedchem.6c00868.
Michał Gałęzowski  1 ,  Maciej Kujawa  2  3  4 ,  Aneta Bobowska  1  5 ,  Matylda Stefaniak-Szałas  1 ,  Joanna Szeremeta-Spisak  1 ,  Marcin Nowogródzki  1 ,  Grzegorz Ćwiertnia  1 ,  Paulina Niedziejko-Ćwiertnia  1 ,  Adam Radzimierski  1 ,  Karolina Gluza  1 ,  Karolina Grycuk  2  6  4 ,  Katarzyna Dziedzic  2 ,  Paulina Węgrzyn  2 ,  Stefan Chmielewski  2 ,  Grzegorz Satała  7 ,  Ewelina Gabor-Worwa  8 ,  Sanja Novak Ratajczak  8 ,  Aniela Gołas  9 ,  Maciej K Rogacki  1 ,  Mateusz Nowak  10 ,  Krzysztof Brzózka  2
Affiliations
  • 1. Department of R&D Chemistry, R&D Center for Innovative Drugs, Ryvu Therapeutics S.A., Kraków30-394, Poland.
  • 2. Department of Biology, R&D Center for Innovative Drugs, Ryvu Therapeutics S.A., Kraków30-394, Poland.
  • 3. Laboratory of Experimental Hematology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Kraków30-387, Poland.
  • 4. Doctoral School of Exact and Natural Sciences, Jagiellonian University, Kraków30-348, Poland.
  • 5. Doctoral School of Science and Technology, Wrocław University of Science and Technology, Wrocław50-370, Poland.
  • 6. Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków30-387, Poland.
  • 7. Department of Compound Screening and Profiling, R&D Center for Innovative Drugs, Ryvu Therapeutics S.A., Kraków30-394, Poland.
  • 8. Department of Drug Metabolism and Pharmacokinetics, R&D Center for Innovative Drugs, Ryvu Therapeutics S.A., Kraków30-394, Poland.
  • 9. Department of In Vivo Research, R&D Center for Innovative Drugs, Ryvu Therapeutics S.A., Kraków30-394, Poland.
  • 10. Early Discovery & Innovation Centre, Drug Discovery Centre, R&D Center for Innovative Drugs, Ryvu Therapeutics S.A., Kraków30-394, Poland.
PMID: 42720492 DOI: 10.1021/acs.jmedchem.6c00868
Abstract

Adenosine is an essential signaling molecule with a well-recognized role in the central nervous, cardiovascular, and immune systems. Its immunosuppressive effects have gained significant attention in oncology, as Adenosine accumulation within the tumor microenvironment can profoundly inhibit antitumor immunity. Therapeutic strategies to counteract this pathway include inhibiting adenosine-generating Enzymes CD39 and CD73 or blocking Adenosine A2A and A2B receptors. In this study, we report the development of compound 45, a novel imidazopyrazine derivative acting as a long-lasting, dual A2A/A2B receptor antagonist with nanomolar in vitro potency. This compound exhibits extended receptor residence time and maintains dual antagonistic activity even at high micromolar Adenosine levels. Compound 45 demonstrates favorable ADME characteristics as well as pharmacokinetic properties, providing high oral bioavailability and systemic exposure across multiple preclinical species. In efficacy studies, this agent robustly reduced metastatic burden in a murine MCA205 pulmonary metastasis model.

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