Michał Gałęzowski, Maciej Kujawa, Aneta Bobowska, Matylda Stefaniak-Szałas, Joanna Szeremeta-Spisak, Marcin Nowogródzki, Grzegorz Ćwiertnia, Paulina Niedziejko-Ćwiertnia, Adam Radzimierski, Karolina Gluza, Karolina Grycuk, Katarzyna Dziedzic, Paulina Węgrzyn, Stefan Chmielewski, Grzegorz Satała, Ewelina Gabor-Worwa, Sanja Novak Ratajczak, Aniela Gołas, Maciej K Rogacki, Mateusz Nowak, Krzysztof Brzózka
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.