Inhibitors And Fluorescent Probes For Protein Kinase Pkac Beta And Its S54l Mutant, Identified In A Patient With Cortisol Producing Adenoma

Recently, a mutation was discovered in the genePRKACBencoding the catalytic subunit beta of PKA (PKAc beta) from a patient with severe Cushing's syndrome. This mutation, S54L, leads to a structural change in the glycine-rich loop of the protein. In the present study, an inhibitor with six-fold selectivity toward S54L-PKAc beta mutant over the wild-type enzyme was constructed. Moreover, we developed a fluorescent assay allowing to determine side by side the affinity of commercially available PKA inhibitors, newly synthesized compounds, and fluorescent probes toward PKAc beta and S54L-PKAc beta.