Year: 2026
Type: article
Abstract: SIRT6, a crucial regulator of aging and cellular homeostasis, represents a promising target for small-molecule activation. In this study, we investigate griseofulvin and its derivatives as novel SIRT6 activators, focusing on the recently developed compound forvisirvat, which has progressed to Phase 2 clinical study. Biochemical evaluation revealed that griseofulvin itself possesses strong SIRT6-activating properties, achieving up to 10-fold activity at 100 μM. Modification of the griseofulvin scaffold generally led to reduced activity, prompting a focus on the oxadiazole moiety of forvisirvat. This strategy produced several analogues with higher potency, the most active at 100 μM being para-1,3,4-oxadiazolephenyl analog 21, which achieved 30-fold SIRT6 activation. Compounds bearing para-substituted phenyl rings exhibited excellent retention of activity at lower concentrations, with para-tolyl derivative 24 being the most potent at 10 μM. Retention of activity at pharmacologically relevant concentrations underscores their potential as potent SIRT6 activators and provides a rationale for continued development as drug candidates.
Institution: University of Ljubljana
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Univerza v Ljubljani
OpenAlex ID: W7139746760
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