Discovery of Forvisirvat (DS-7830a/SP-624), a Brain-Penetrant Sirtuin 6 Activator Derived from Griseofulvin with Antidepressant-Like Effects

We report the discovery of forvisirvat (DS-7830a/SP-624), a potent and selective brain-penetrant activator of sirtuin 6 (SIRT6) derived from natural product griseofulvin. Photoaffinity labeling combined with molecular docking identified an allosteric binding site that overlaps with the substrate myristoyl pocket. SAR studies focused on C-6 modification yielded forvisirvat with markedly improved pharmacokinetic properties and CNS exposure. Forvisirvat selectively activated SIRT6 over other sirtuin isoforms and exhibited robust antidepressant-like effects in mouse models, supporting the therapeutic potential of SIRT6 activation in depression.