Discovery of Potent 1,3-Cyclobutane-Containing Dual A_2A/A_2B Receptor Antagonists with Low Projected Human Dose for...

Area of Science:

• Medicinal Chemistry
• Immunology
• Pharmacology

Background:

• Tumor microenvironment often causes immunosuppression, enabling tumor immune evasion.
• This immunosuppression can lead to resistance to immuno-oncology therapies.
• Adenosine receptors A2A and A2B play a role in mediating this immunosuppression.

Purpose of the Study:

• To develop potent and selective dual antagonists for adenosine receptors A2A and A2B.
• To improve pharmacokinetic and solubility profiles of lead compounds.
• To explore combination therapy with checkpoint inhibitors for enhanced anti-tumor immunity.

Main Methods:

• Design and synthesis of novel dual A2A/A2B receptor antagonists.
• Utilized a 1,3-cyclobutane linker for optimal molecular structure.
• Employed high-throughput experimentation (HTE) for efficient chemical synthesis and optimization.
• Evaluated compound potency, selectivity, and pharmacokinetic properties.

Main Results:

• Identified a lead molecule (compound 34) with a favorable balance of potency and physicochemical properties.
• Compound 34 exhibited an exceptional effective half-life across multiple species.
• Developed efficient late-stage synthetic routes for complex derivatives using HTE.

Conclusions:

• Dual A2A/A2B receptor antagonists show promise for overcoming adenosine-mediated immunosuppression in the tumor microenvironment.
• The developed compounds offer improved drug-like properties for potential therapeutic applications.
• This work provides a foundation for novel combination strategies in immuno-oncology.