3 research outputs found
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 <i>O</i>-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
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 <i>O</i>-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 <i>O</i>-acyltransferase
Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors
Porcupine is an <i>O</i>-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