Discovery of Pyridinone Derivatives as Potent, Selective, and Orally Bioavailable Adenosine A 2A Receptor Antagonists for Cancer Immunotherapy.

Recent studies and clinical evidence have strongly supported the development of adenosine A 2A receptor (A 2A R) antagonists as novel approaches for cancer immunotherapy. By screening our in-house compound library, a pyridinone hit compound ( 1 ) with weak A 2A R 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 2A R antagonistic activity (IC 50 = 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 2A R antagonist candidate for cancer immunotherapy.