GSK-J4 is the ester prodrug of the active (acid) component GSK-J1. The ester is designed to facilitate entry into cells where it is rapidly hydrolysed to the active acid and studies from the authors demonstrate rapid hydrolysis in macrophages, the systems studied. They also note that in other cell systems, the degree and rate of conversion to acid should be assessed to ensure data generated is not misleading. It is a cell active inhibitor of KDM6 although more recently it has been demonstrated to exhibit inhibition of KDM5, albeit weaker. It can be recommended as a cell target probe with the caveats around moderate KDM selectivity, dependence on ester cleavage for activity, and also a not ideal level of target potency even when hydrolysed in cells.
20 Jun 2016 )