Chemical Evolution of Aplithianine Class of Serine/Threonine Kinase Inhibitors

Chimeric kinase J-PKAcα represents a potential
therapeutic
target for fibrolamellar hepatocellular carcinoma (FLHCC). Structure-based
design and screening were applied to improve the potency of the marine-derived
kinase inhibitor aplithianine A targeting J-PKAcα. Three classes
of aplithianines (I, II, and III) including >150 analogs were synthesized,
significantly improving biochemical IC50 values to the
low nanomolar range. X-ray diffraction experiments confirmed that
the class II aplithianines adopted a novel binding mode to J-PKAcα
by interacting with the DFG residue Asp239. The kinase selectivity
profiles were assessed by kinome profiling. In vitro profiles of selected class II analogs were evaluated to determine
compound solubility, protein binding, permeability, metabolism, and
hERG binding. Selected aplithianine analogs inhibited intracellular
phosphorylation of the peptide substrate CREB following stimulation
of the J-PKAcα fusion kinase in NIH/3T3 cells and exhibited
antiproliferative/cytotoxic activities against select cancer cell
lines from the NCI-60 cell panel at nanomolar concentrations.