NVS-PAK1-1

NVS-PAK1-1 is a potent PAK1 inhibitor with exclusive selectivity for this kinase. Structural studies revealed an allosteric binding mode. This inhibitor is highly potent in cellular assays but showed poor stability in vivo. Thus, in vivo use is not recommended without further improvement of pharmacological properties. It is an excellent inhibitor for functional studies on PAK1 kinase.

NVS-PAK1-1 is a potent, allosteric PAK1 inhibitor. It is about 60-fold selective over PAK2. It is highly selective over other kinases in the kinome. It has a submicromolar IC50 in a PAK1 autophosphorylation assay. These features make it a useful tool to assess the impact of PAK1 inhibition in a cellular context. More data would need to be collected, but poor microsomal stability (rat) suggests the compound may not be suitable for use in model organisms (in vivo applications).

Rudolph et al., J Med Chem 2016 demonstrate that class I PAK inhibitors from two structurally distinct classes reveal persistent cardiovascular toxicity and correlate minimum toxic concentrations with PAK1/2-mediated cellular potencies. Broad screening of selected PAK inhibitors reveals that PAK1, 2, and 3 as the only overlapping targets. This data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition. This manuscript cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery.