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Irreversible Antagonists for the Adenosine A2B Receptor
Ahmed Temirak1, Jonathan G Schlegel1, Jan H Voss1
1PharmaCenter Bonn & Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Molecules (Basel, Switzerland)
|June 24, 2022
Summary
Researchers developed novel irreversible antagonists targeting the adenosine A2B receptor (A2BAR) for cancer immunotherapy. Compound 6a demonstrated potent and selective blockade, offering a promising new therapeutic avenue.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Immunotherapy
Background:
- Adenosine A2B receptor (A2BAR) blockade is a potential cancer immunotherapy strategy.
- Development of selective and potent A2BAR antagonists is crucial for therapeutic applications.
Purpose of the Study:
- To design, synthesize, and characterize novel irreversible A2BAR antagonists.
- To evaluate their potency, selectivity, and binding kinetics.
- To investigate the interaction mechanism with the A2BAR.
Main Methods:
- Synthesis of 8-p-sulfophenylxanthine derivatives.
- Radioligand binding assays.
- Bioluminescence resonance energy transfer (BRET)-based assays for Gα15 protein activation.
- Ligand wash-out and kinetic experiments.
- Site-directed mutagenesis (K269L).
Main Results:
- Compound 6a (PSB-21500) identified as a potent (Ki 10.6 nM) and selective irreversible A2BAR antagonist.
- Compound 6c showed similar potency but lacked selectivity.
- A reversible antagonist (12) was also developed.
- Irreversible antagonists do not appear to interact with the K269 residue.
Conclusions:
- Novel irreversible A2BAR antagonists were successfully synthesized and characterized.
- Compound 6a is a valuable tool and potential therapeutic lead for cancer immunotherapy.
- Further development of these antagonists is warranted.
Keywords:
BRET assayG protein activationG protein-coupled receptorGα15adenosinecovalent bindingmutagenesisradioligand binding studiessynthesisxanthineMore Related Videos
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