Discovery of Pyridinone Derivatives as Potent, Selective, and Orally Bioavailable Adenosine A2A Receptor Antagonists for Cancer Immunotherapy

Recent studies and clinical evidence have strongly supported the development of adenosine A_2A receptor (A_2AR) antagonists as novel approaches for Cancer Immunotherapy. By screening our in-house compound library, a pyridinone hit compound (1) with weak A_2AR antagonistic activity was identified. Further structure-activity relationship studies revealed a series of pyridinone derivatives with strong potency. Compound 38 stood out with a potent A_2AR antagonistic activity (IC₅₀ = 29.0 nM), good mouse liver microsomal metabolic stability (t_1/2 = 86.1 min), and excellent oral bioavailability (F = 86.1%). Of note, 38 effectively enhanced the activation and killing ability of T cells in vitro by down-regulation of immunosuppressive molecules (LAG-3 and TIM-3) and up-regulation of effector molecules (GZMB, IFNG, and IL-2). Moreover, 38 exhibited excellent in vivo antitumor activity with a tumor growth inhibition (TGI) of 56.0% in the MC38 tumor model via oral administration, demonstrating its potential as a novel A_2AR antagonist candidate for Cancer Immunotherapy.