A dual A2A/A2B antagonist chemotype that sensitizes MSS colorectal tumors to anti-PD-1
- Imidazo[1,2-a]pyrazine-ureas emerged as a new chemotype of dual A2A/A2B adenosine receptor antagonists.
- SAR showed that iodination at the 3-position of the core improved affinity and functional antagonism; simulations suggest distinct binding modes in the two orthosteric pockets.
- The lead restored T-cell cytokine production, increased T-cell infiltration, and boosted anti-PD-1 efficacy in CD73-high colorectal models.
💡 Points
Dual A2A/A2B blockade makes sense in CD73-high tumors, where adenosine hits both receptors, but A2B selectivity versus A1 and A3 is usually the hard part. A 3-iodo group is a flag for me: it helps affinity but invites questions about metabolic stability and lipophilic efficiency. Whether the iodine can be swapped for a smaller or less lipophilic group is the next experiment.