Pharmacophore Model for Wnt/Porcupine Inhibitors and Its Use in Drug Design

Porcupine is a component of the Wnt
pathway which regulates cell proliferation, migration, stem cell self-renewal,
and differentiation. The Wnt pathway has been shown to be dysregulated
in a variety of cancers. Porcupine is a membrane bound O-acyltransferase that palmitoylates Wnt. Inhibiting porcupine blocks
the secretion of Wnt and effectively inhibits the Wnt pathway. Using
high throughput screening, we have identified a number of novel porcupine
inhibitors with diverse scaffolds. The pharmacophore requirements
for our porcupine inhibitors were elucidated, and a pharmacophore
model is proposed. Our compounds as well as all currently published
porcupine inhibitors may be fitted to this model in low energy conformations
with good superimposition of the pharmacophore elements. The model
also explains the stereochemical requirements of our chiral porcupine
inhibitors. The pharmacophore model was successfully used for designing
3 new series of porcupine inhibitors having a tricyclic xantine, a
phtalimide, or a piperidine–maleimide scaffold.