Inupadenant is an orally active, highly selective A2A receptor antagonist, which maintains full potency at the high adenosine levels found in tumors, exhibiting strong antitumor activity[1-2]. Inupadenant is not brain-penetrant[1].
In vitro, treatment with 10nM Inupadenant for 45 minutes antagonized A2AR signaling and reduced CREB phosphorylation in T and B lymphocytes[3]. Treatment with 300nM Inupadenant for 3 days restored A2AR-mediated suppression of B cells differentiation to Antibody-Secreting Cells (ASCs), both at the level of PBs and PCs[3]. Inupadenant has an IC50 value of 0.73nM against HEK293 cells stably expressing human A2AR(HEK293-hA2AR), an IC50 value of 575nM against H293-hA2B, and an IC50 value of 192nM against CHO-K1-hA1[3].
In vivo, Inupadenant (0.6mg/kg/d; p.o.), in combination with chemotherapy, demonstrated tumor growth inhibition in mouse tumor models with subcutaneous implantation of MCA205 or CT26 cells[4].
References:
[1] Laurence Buisseret, et al. Phase 1 trial of the adenosine A2Areceptor antagonist inupadenant (EOS-850): Update on tolerability, and antitumor activity potentially associated with the expression of the A2A receptor within the tumor. Journal of Clinical Oncology. Volume 39, Issue 15_suppl.
[2] The A2AR antagonist inupadenant promotes humoral responses in preclinical models. Abstract 48P. Presented at: ESMO Immuno-Oncology Congress 2024; December 2024; Geneva, Switzerland.
[3] Tieppo P, Shehade H, Martinoli C, et al. Inhibition of A2AR alleviates adenosine-mediated suppression of plasma cell differentiation. Front Immunol. 2025;16:1702402.
[4] 34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019): part 2 : National Harbor, MD, USA. 10 November 2019. J Immunother Cancer. 2019;7(Suppl 1):283.
Inupadenant是一种口服有效的、高度选择性的A2A受体拮抗剂，能在肿瘤中发现的高浓度腺苷环境中保持完全的活性，表现出强大的抗肿瘤作用[1-2]。Inupadenant不能透过血脑屏障[1]。
在体外实验中，10nM的Inupadenant处理45分钟拮抗了A2AR信号传导，并降低了T和B淋巴细胞中CREB蛋白磷酸化[3]。300nM的Inupadenant处理3天，在骨髓外周血和骨髓细胞水平上恢复了A2AR介导的对B细胞向抗体分泌细胞（ASCs）分化的抑制作用[3]。Inupadenant对稳定表达人类A2AR的HEK293细胞（HEK293-hA2AR）的IC50值为0.73nM，对H293-hA2B的IC50值为575nM，对CHO-K1-hA1的IC50值为192nM[3]。
在体内实验中，Inupadenant（0.6毫克/千克/天；口服）与化疗药物联合使用，在小鼠肿瘤模型（皮下植入MCA205或CT26细胞）中显示出肿瘤生长抑制作用[4]。