Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors

Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine
may block the Wnt pathway which is often dysregulated in various cancers.
Consequently porcupine inhibitors are thought to be promising oncology
therapeutics. A high throughput screen against porcupine revealed
several potent hits that were confirmed to be Wnt pathway inhibitors
in secondary assays. We developed a pharmacophore model and used the
putative bioactive conformation of a xanthine inhibitor for scaffold
hopping. The resulting maleimide scaffold was optimized to subnanomolar
potency while retaining good physical druglike properties. A preclinical
development candidate was selected for which extensive in vitro and in vivo profiling is reported.