Discovery of Dual A2A/A2B Adenosine Receptor Antagonist and Clinical Candidate INCB106385.

Suppression of immune checkpoint pathways enables tumor cells to take over immunoregulatory functions, promoting cell growth and proliferation. Elevated adenosine production in the tumor microenvironment suppresses immune checkpoint control through activation of A2A adenosine receptors on immune cells. While A2A antagonists originally developed for CNS indications have entered oncology, their potency may be insufficient to challenge locally high adenosine concentrations within the tumor microenvironment for receptor occupancy. Here, we describe the discovery of INCB106385 (36), a potent dual A2A/A2B antagonist identified from in-house screening efforts. Compound 36 exhibits high potency at both receptors, favorable drug-like properties, and limited CNS penetration. In preclinical studies, it demonstrated robust pharmacokinetics across species and significant efficacy in a multiday CT26 mouse colon carcinoma model. These findings supported the advancement of INCB106385 into Phase 1 clinical trials (NCT04580485, NCT04989387) for cancer immunotherapy.