GSK716 (GSK-716) is a potent inhibitor of Z α1‐antitrypsin polymerisation, binds to Zα1‐antitrypsin with a high‐affinity (pKD=8.5).
GSK716 completely blocked the intracellular formation of Zα1‐antitrypsin polymers as measured by staining with the 2C1 anti‐Z α1‐antitrypsin polymer monoclonal antibody (pIC50=6.3).
GSK716 also increased the secretion of Z α1‐antitrypsin (pEC50=6.2). GSK716 exhibited a good level of selectivity over the off‐target panel and over other serpins.
GSK716 binds to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway.
GSK716 reduces intracellular polymerisation and increases the secretion of Z α1‐antitrypsin threefold in a transgenic mouse model of Z α1‐antitrypsin deficiency.
