Repurposing Ilaprazole as a PP5 TPR Domain Binder with Modulatory Effects on MAPK Signaling.

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Small-molecule modulators of the protein phosphatase 5 (PP5) tetratricopeptide repeat (TPR) domain are underexplored.
• Targeting PP5 offers a potential strategy for modulating cellular signaling pathways.

Purpose of the Study:

• To identify and characterize small-molecule binders of the PP5 TPR domain.
• To investigate the pharmacological effects of ilaprazole on PP5-associated signaling in cancer cells.

Main Methods:

• Fluorescence polarization-based competitive screening to identify PP5 TPR domain binders.
• Biophysical assays and molecular docking to confirm and characterize binding interactions.
• Cell-based assays in KRAS mutant colorectal cancer cells to assess signaling modulation.

Main Results:

• Ilaprazole was identified as a PP5 TPR domain binder, distinct from other proton pump inhibitors.
• Ilaprazole engaged cellular PP5, reduced RAF stability, and suppressed MAPK signaling in colorectal cancer cells.
• Ilaprazole demonstrated minimal single-agent efficacy but sensitized cells to binimetinib, a MEK inhibitor.

Conclusions:

• The PP5 TPR domain is a druggable target for small-molecule intervention.
• Ilaprazole serves as a lead scaffold for developing novel PP5 modulators.
• Ilaprazole enhances the efficacy of MEK inhibitors in KRAS mutant colorectal cancer.