Abstract 4135: Novel dual A2A A2B adenosine receptor antagonists for cancer immunotherapy: in vitro and in vivo characterization

Abstract

Adenosine is important messenger molecule that is involved in signal transmission in central nervous, cardiovascular and immunological systems. The immunosuppressive role of adenosine attract attention of many researchers recently and reversal of that effect is addressed by several different approaches i.e.: inhibition of enzymes that are producing the adenosine in tumor microenvironment like CD39 and CD73 but also the antagonization of adenosine receptors mainly A2A and A2B subtypes. Here we present a novel series of unsurmountable, dual A2A/A2B antagonists that retain its nanomolar potency in tumor-like adenosine-rich environment. This advantageous profile comes mainly from long residence time in adenosine receptors which transfers into high receptor occupancy even after full clearance of the compound from plasma. We are demonstrating how our inhibitors restore adenosine depleted immune functionality in the series of functional in vitro assays in primary cells. This includes the cytokine release by activated CD4+ and CD8+ human T-lymphocytes (driven by A2A) and dendritic cells (driven by A2B). Most importantly presented compounds show improved in vivo pharmacological profile in comparison to adenosine inhibitors currently tested in clinical trials manifested by high inhibition of CREB phosphorylation in mouse model. Citation Format: Michal Galezowski, Paulina Węgrzyn, Aneta Bobowska, Katarzyna Dziedzic, Joanna Szeremeta-Spisak, Marcin Nowogrodzki, Grzegorz Satala, Alicja Obara, Iwona Lozinska-Raj, Marcelina Dudek, Anita Janiga, Jacek Reus, Marek Wronowski, Magdalena Zastawna, Grzegorz Statkiewicz, Maciej Rogacki, Magdalena Ziembik, Karolina Grycuk, Foteini Soukou, Kinga Michalik, Agnieszka Adamus, Karolina Wiatrowska, Natalia Lewandowska, Aniela Golas, Olga Haberkiewicz, Rod Porter, Krzysztof Brzozka, Mateusz Nowak. Novel dual A2A A2B adenosine receptor antagonists for cancer immunotherapy: in vitro and in vivo characterization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4135.

Adenosine A2A Receptor Antagonists for Cancer Immunotherapy

“…Further results from in vivo testing were disclosed for compound 44. 138 It was somewhat more potent than AB928 in inhibiting CREB phosphorylation in C57BL/6 mice even 12 h after administration (50 mg/kg for compound 44 and 100 mg/kg for AB928). Additionally, compound 44 showed an excellent PK profile (t 1/2 = 3.6 h, C max = 23 000 ng/mL, AUC = 6500 ng•h/mL at 3 mg/kg, po, in mice) and antitumor effects on B16-F10/CT26 tumor models.…”

“…Notably, both compounds 43 and 44 exclusively restored the function of monocyte-derived dendritic cells (moDC cells, driven by A 2B R) compared to A 2A R antagonists such as CPI-444. Further results from in vivo testing were disclosed for compound 44 . It was somewhat more potent than AB928 in inhibiting CREB phosphorylation in C57BL/6 mice even 12 h after administration (50 mg/kg for compound 44 and 100 mg/kg for AB928).…”

Design, Synthesis, and Bioevaluation of 2-Aminopteridin-7(8H)-one Derivatives as Novel Potent Adenosine A2A Receptor Antagonists for Cancer Immunotherapy

“…Although several A 2A R antagonists are under clinical trials for cancer immunotherapy, some of them dramatically lose potency when exposed to high level of adenosine. − Earlier findings by Jonathan et al have shown that the concentration of adenosine in the extracellular fluid of solid carcinomas may reach a micromolar level (10–100-fold higher than normal concentration) . Generally, the concentration of adenosine in the TME is also higher than that in the pathological conditions of PD .…”