Kinase-Inhibitor Inspiration Yields Ultra-Selective Adenosine A3 Receptor Blockers
- Starting from the CDK inhibitor roscovitine, the team built a large library of trisubstituted triazolopyridazines and found they act as selective antagonists of the adenosine A3 receptor, not as kinase inhibitors.
- Of the many analogues made, the best bind the receptor at extremely low concentrations and discriminate strongly against the A1, A2A and A2B subtypes.
- SAR analysis points to the substituent patterns that favor potency, and docking places the series in the orthosteric site shared with the agonist IB-MECA.
- The lead, Triskelline A-143, shows a favorable pharmacological and safety profile.
💡 Points Based on the abstract
It is a pleasant surprise to see a kinase-inspired scaffold this clean on a GPCR. If selectivity holds in orthogonal assays, the roscovitine-derived core is an easily decorated starting point, and three-vector SAR on a triazolopyridazine is cheap to run. The pose shared with IB-MECA comes from docking alone, so I would hold off until mutagenesis or a structure backs it.