Yasuyuki Ogawa, Keiji Saito, Katsuyoshi Nakajima, Osamu Iwamoto, Kazumasa Aoki, Mitsuhiro Makino, Shinji Tanaka, Nobuya Kurikawa, Eriko Michishita-Kioi, Seiko Nagata, Yoko Fujita, Masato Sasaki, Akiko Kasahara, Isao Yasumatsu, Makoto Hirasawa, Wataru Saitoh
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.