Discovery of MK-1088 as a Potent A_2A/A_2B Adenosine Receptor Dual-Antagonist for Cancer Immunotherapy

Immune cells expressing the adenosine A_2A receptor (A_2AR) and A_2B receptor (A_2BR) present in an adenosine-rich tumor microenvironment have suppressed effector functions, such as proinflammatory cytokine release, antigen presentation, and others, making them inert to cancer cells. Simultaneous blockade of the downstream effects mediated by both receptor subtypes with a dual inhibitor has the potential to reverse adenosine-mediated suppression of tumor immune surveillance as either a single-agent treatment or in combination with other immunotherapy agents such as anti-PD-1/PD-L1 monoclonal antibodies. This publication describes the discovery and optimization of a novel series of potent and selective dual A_2AR/A_2BR antagonists, resulting in compound 46 (MK-1088) being identified for progression to human clinical studies.