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

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• Atypical protein kinase C-iota (PKC-ι) is a key enzyme implicated in various cancers.
• PKC-ι is recognized as a promising target for novel anticancer therapies.

Purpose of the Study:

• To optimize a weakly inhibiting pyridine fragment into a potent PKC-ι inhibitor.
• To elucidate the binding mode of the optimized inhibitor using X-ray crystallography.

Main Methods:

• High-concentration biochemical screening to identify initial inhibitors.
• Structure-activity relationship studies and molecular docking for optimization.
• X-ray crystallography to determine the protein-ligand complex structure.

Main Results:

• A pyridine fragment was optimized from a weak inhibitor (IC50=424 μM) to a potent PKC-ι inhibitor (IC50=270 nM).
• X-ray crystal structure analysis revealed a unique binding mode involving the post-kinase domain of PKC-ι.

Conclusions:

• The study successfully optimized a fragment into a potent PKC-ι inhibitor.
• The identified unique binding mode provides valuable insights for future anticancer drug design targeting PKC-ι.