Fragment-based Discovery of a Small-Molecule Protein Kinase C‑iota Inhibitor Binding Post-kinase Domain Residues

The
atypical protein kinase C-iota (PKC-ι) enzyme is implicated
in various cancers and has been put forward as an attractive target
for developing anticancer therapy. A high concentration biochemical
screen identified pyridine fragment weakly inhibiting PKC-ι
with IC50 = 424 μM. Driven by structure–activity
relationships and guided by docking hypothesis, the weakly bound fragment
was eventually optimized into a potent inhibitor of PKC-ι (IC50= 270 nM). Through the course of the optimization, an intermediate
compound was crystallized with the protein, and careful analysis of
the X-ray crystal structure revealed a unique binding mode involving
the post-kinase domain (C-terminal tail) of PKC-ι.