Anales RANF

P.11 A 2B ANTAGONIST AS ANTIMETASTATIC AGENTS: DESIGN, SYNTHESIS AND OPTIMIZATION OF NOVEL CHEMOTYPES R. Prieto, 1 M. Chotalia, 1 M. Majellaro, 1 M. J. Núñez, 1 S. Novio, 1 J. Azuaje, 1 C. García- Santiago, 1 M. Freire-Garabal, 1 M.I. Loza, 1 J. Brea, 1 H. Gutiérrez de Terán, 2 X. García- Mera 1 and E. Sotelo 1 1 . Universidade de Santiago de Compostela, Santiago de Compostela, Spain; 2 . Uppsala University, Uppsala, Sweden. Adenosine is a key immunosuppressive metabolite that regulates one of the major mechanisms supporting immune tolerance in tumors. 1 In normal cells, A 2A and A 2B receptors are engaged in the regulatory mechanisms that protects tissues against excessive immune reactions. 1,2 However, in the tumour microenvironment elevated adenosine concentration hijacks this protective pathway, hindering anti-tumour immunity. 2 Adenosine inhibits the biological functions of T lymphocytes, infiltrating the cancer tissue by binding to the A 2A receptor. In addition, activation of A 2B receptor reduce the response of dendritic cells and other parts of the innate immune system. Accordingly, A 2A and A 2B receptor antagonists constitute an emerging family of immunotherapeutic agents for cancer treatment. 1,2 Within the frame of a project aimed at the discovery of A 2B AR antagonists for cancer immunotherapy, 3 we herein document the identification and optimization of diverse chemotypes inspired in ISAM-140, a highly potent and specific A 2B AR ligand developed in our laboratory. Some of the identified ligands combine potent A 2B affinity and attractive antimetastatic effect in different cell lines. Structure of model ligands and synthetic strategy employed to prepare the new chemotypes. References: [1] Vijayuan, D., Young, A., Teng, M. W., Smyth, M., Nat. Rev. Cancer , 2017, 17 , 709-725. [2] Leone, R. D., Amens, L. A., J. ImmunoTher. Cancer , 2018, 6 , 57-66. [3] Crespo, A. El Maatougui, A. Biagini, P. Azuaje, J. Coelho, A. Brea, J. Loza, M. I. Cadavid, M. I. García-Mera, X. Gutiérrez-de-Terán, H. Sotelo, E. ACS Med. Chem. Lett . 2013, 4, 1031–1036. El Maatougui, A., Azuaje, J., González-Gómez, M., Miguez, G., Crespo, A., Carbajales, C, Escalante, L., Gutiérrez de Terán, H., Sotelo, E., J. Med. Chem ., 2016, 59, 1967-1983. Carbajales, C., Azuaje, J., Oliveira, A., Loza, M. I., Brea, J., Cadavid, M.I., Masaguer, C.F., García-Mera, X., Gutiérrez de Terán, H., Sotelo, E., J. Med. Chem ., 2017, 60 , 3372-3382.