Selisistat (6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide, SEN0014196, EX-527) is a selective SirT1 inhibitor that inhibits recombinant human SirT1 with an IC50 of 98 nm. It is more than 200-fold selective over SirT2 and SirT3 and has been shown to inhibit deacetylation of several SirT1 substrates both in vitro and in vivo. The compound exhibits cyto- and neuroprotective activity against toxicity induced by mutant HTT in cellular and in vivo models of HD increasing survival, amelioration of psychomotor behaviour and improvement in histopathological endpoints in the most widely employed animal models of HD. In a previous clinical study, selisistat was shown to be well tolerated at single doses up to 600 mg and repeated doses up to 300 mg day−1 for up to 7 days to healthy volunteers. The availability of selective, safe SirT1 inhibitors such as selisistat therefore makes the acetylation-dependent clearance of mutant HTT a clinically testable therapeutic approach.
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