A_2B Adenosine Receptor Antagonists with Picomolar Potency

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cancer Immunotherapy

Background:

• The adenosine A2B receptor (A2B AR) is a potential target for cancer (immuno)therapy due to its roles in proliferation, angiogenesis, metastasis, and immune response.
• Xanthin-8-yl-benzenesulfonamides are a class of compounds explored for their potential as A2B AR modulators.

Purpose of the Study:

• To explore structure-activity relationships of xanthin-8-yl-benzenesulfonamides for A2B AR antagonism.
• To synthesize novel compounds with high affinity and selectivity for the A2B AR.
• To develop a potent and selective A2B AR antagonist for preclinical cancer research.

Main Methods:

• Synthesis of novel xanthin-8-yl-benzenesulfonamide derivatives using a convergent strategy.
• Evaluation of binding affinity and selectivity for human and mouse A2B AR subtypes.
• Computational studies to predict binding interactions.

Main Results:

• A series of new compounds with subnanomolar affinity and high selectivity for A2B AR were synthesized.
• Compound 34 (PSB-1901) demonstrated exceptional potency (Ki 0.0835 nM) and >10,000-fold selectivity against other adenosine receptor subtypes.
• Compound 34 exhibited similar potency and selectivity in mouse models, indicating its potential for preclinical studies.
• Functional groups were incorporated for potential attachment of reporter molecules.

Conclusions:

• Novel xanthin-8-yl-benzenesulfonamides were successfully synthesized and characterized as potent A2B AR antagonists.
• Compound 34 (PSB-1901) represents a highly promising lead compound for developing A2B AR-targeted cancer immunotherapies.
• The findings support the therapeutic potential of targeting A2B AR in cancer treatment.