Synonyms: GS-0976 | GS-ACC | ND 630 [4] | ND-630 | NDI-010976
Compound class:
Synthetic organic
Comment: Firsocostat (GS-0976) is a liver-directed acetyl-CoA carboxylase (ACC) inhibitor [2]. It was initially identified by Nimbus Therapeutics [3], and is being developed by Gilead as an antilipemic agent for potential to treat non-alcoholic steatohepatitis (NASH) [1]. Firsocostat is an allosteric inhibitor that binds to the ACC biotin carboxylase dimerization site, rather than to the previously targeted carboxyltransferase domain. The firsocostat-ACC interaction mimics the physiological inhibition of ACC by AMPK.
Ligand Activity Visualisation ChartsThese are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts. ✖ |
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Bioactivity Comments |
In the mouse model of NASH (MC4R knockout) pharmacological inhibition of ACC1/2 by firsocostat (GS-0976) improves hepatic lipid metabolism and ameliorates steatosis and hepatic fibrosis [6]. This effect is also observed in human clinical trial patients [5]. ACC1 and ACC2 are both inhibited by firsocostat. GS-0976-mediated ACC inhibition is highly specific for ACC; no effect on the activity of 101 enzymes, receptors, growth factors, transporters, and ion channels in the Ricerca DrugMatrix screening panel was detected [3]. Since the allosteric binding site for firsocostat is not present (conserved) in other mammalian carboxylases it does not inhibit these mechanistically related enzymes. |
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