This probe has been developed by a strong medicinal chemistry approach for which more than 180 analogs have been profiled in in vitro KAT6A activity assays (Priebbenow J Med Chem 2020). WM-1119 is a highly potent KAT6A inhibitor with high selectivity over KAT5 and KAT7. A crystal structure confirms the binding mode as an acetyl-CoA competitive inhibitor. No detailed SAR data compared to KAT6B have been reported, but the authors state that limited testing suggests these compounds behaves as dual KAT6A/B inhibitor. The compound has further been profiled against a panel of 159 targets where no other affinities have been detected. However, no general methods like interaction proteomics or thermal proteome profiling for comprehensively identifying interactors have been identified. Considering that the compound acts as a competitive inhibitor of acetyl-CoA, it will be important to profile whether other acetyl-CoA binders are also interacting with WM-1119.
Cellular data reported for this compound rely on the measurement of indirect effects like growth inhibition and expression changes, whereas direct measurement of acetylation changes has only been reported for the analog WM-8014.
Detailed characterization of physicochemical and pharmacological parameters including solubility, plasma protein binding, microsome stability and permeability and plasma concentrations after IV and oral dosing in rat and IP dosing in mice are available.
28 Aug 2020 )