CPI-444 (V81444) is an orally available A2AAR antagonist with a Ki value of 3.54nM[1]. CPI-444 blocks the induction of cAMP by 1.5nM 5′-(N-Ethylcarboxamido) adenosine (NECA) with an IC50 value of 17.03nM[2]. CPI-444 inhibits the adenosine methionine (ADO) signaling pathway by antagonizing the A2AAR in the tumor microenvironment, stimulating the immune response mediated by T cells, thereby leading to tumor regression[3]. CPI-444 has been widely used to restrain tumor growth and metastasis, and to enhance oncolytic immunotherapy in animal models[4].
In vitro, CPI-444 treatment (10µM) for 1 hour significantly inhibited the suppressive effect of NECA on IFN-γ and IL-2 release from human peripheral blood mononuclear cells (hPBMCs)[2].
In vivo, daily oral administration of CPI-444 at a dose of 10mg/kg for 5 consecutive days enhanced the immune response to vaccinia-OVA and strengthened the memory response to viral infection in mice[5].
References:[1] Zhang J, Yan W, Duan W, et al. Tumor immunotherapy using A2A adenosine receptor antagonists[J]. Pharmaceuticals, 2020, 13(9): 237.
[2] Willingham S B, Ho P Y, Hotson A, et al. A2AR antagonism with CPI-444 induces antitumor responses and augments efficacy to anti-PD-(L) 1 and anti-CTLA-4 in preclinical models[J]. Cancer immunology research, 2018, 6(10): 1136-1149.
[3] Deb P K, Maity P, Sarkar B, et al. Insights from clinical trials on A2A adenosine receptor antagonists for cancer treatment[J]. ACS Pharmacology & Translational Science, 2025, 8(6): 1498.
[4] Wu Y, Lin J Y, Zhou Y D, et al. Oncolytic peptide‐nanoplatform drives oncoimmune response and reverses adenosine‐induced immunosuppressive tumor microenvironment[J]. Advanced Healthcare Materials, 2024, 13(26): 2303445.
[5] Leone R D, Sun I M, Oh M H, et al. Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models[J]. Cancer immunology, immunotherapy, 2018, 67(8): 1271-1284.