Journal of Medicinal Chemistry· 2026Q1
Imidazo[1,2- a ]pyrazine Derivatives as Dual A2A/A2B Adenosine Receptor Antagonists Enhancing Anti-PD-1 Antibody Therapy in Colorectal Cancer
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- Q1SCImago
- 2026year
Short summary
New imidazo[1,2-a]pyrazine-urea derivatives (e.g., compound 5p) act as dual antagonists for A2A and A2B adenosine receptors, enhancing anti-PD-1 therapy efficacy in colorectal cancer models.
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Key points
- Identified imidazo[1,2-a]pyrazine-urea derivatives as a new chemotype targeting both A2A and A2B adenosine receptors.
- Compound 5p, with a 3-iodo substituent, showed enhanced affinity and functional antagonism for both receptor subtypes.
- In CRC models, 5p restored anti-tumor immune responses, including Th1 cytokine production and T cell infiltration.
- 5p potentiated the efficacy of anti-PD-1 therapy in CD73-high colorectal cancer models, suppressing tumor growth.
AI-generated from the title and abstract; the full text is not read.
Abstract
Abstract Adenosine signaling through A2A and A2B adenosine receptors (ARs) suppresses antitumor immunity and promotes tumor progression, limiting immune checkpoint blockade in microsatellite-stable colorectal cancer (CRC). Here, we identified imidazo[1,2-a]pyrazine-urea derivatives as a new chemotype of dual hA2A/hA2B AR antagonists. SAR studies revealed that 3-iodination of the core scaffold enhanced receptor affinity and functional antagonism, with 5p emerging as a representative lead. MD simulations showed that 5p can be accommodated in the orthosteric pockets of both AR subtypes through distinct binding modes, with the 3-iodo substituent occupying adjacent subpockets. Representative compounds inhibited adenosine-induced CREB phosphorylation, restored Th1 cytokine production, and increased CD4+ and CD8+ T cell infiltration. In CD73-high CRC models, 5p suppressed tumor growth and potentiated anti-PD-1 efficacy. These findings support dual A2A/A2B AR antagonism as a strategy to reprogram the adenosine-rich tumor microenvironment and improve CRC immunotherapy.
The authors' abstract, as published at the source. Journal of Medicinal Chemistry, 2026 · DOI ↗
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