Discovery and Optimization of a Porcupine Inhibitor

Wnt
proteins regulate various cellular functions and serve distinct
roles in normal development throughout life. Wnt signaling is dysregulated
in various diseases including cancers. Porcupine (PORCN) is a membrane-bound O-acyltransferase that palmitoleates the Wnts and hence
is essential for their secretion and function. The inhibition of PORCN
could serve as a therapeutic approach for the treatment of a number
of Wnt-dependent cancers. Herein, we describe the identification of
a Wnt secretion inhibitor from cellular high throughput screening.
Classical SAR based cellular optimization provided us with a PORCN
inhibitor with nanomolar activity and excellent bioavailability that
demonstrated efficacy in a Wnt-driven murine tumor model. Finally,
we also discovered that enantiomeric PORCN inhibitors show very different
activity in our reporter assay, suggesting that such compounds may
be useful for mode of action studies on the PORCN O-acyltransferase.