title: Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer.
abstract: Porcupine (PORCN) is a membrane bound O-acyltransferase that is required for Wnt palmitoylation, secretion, and biologic activity. All evaluable human Wnts require PORCN for their activity, suggesting that inhibition of PORCN could be an effective treatment for cancers dependent on excess Wnt activity. In this study, we evaluated the PORCN inhibitor Wnt-C59 (C59), to determine its activity and toxicity in cultured cells and mice. C59 inhibits PORCN activity in vitro at nanomolar concentrations, as assessed by inhibition of Wnt palmitoylation, Wnt interaction with the carrier protein Wntless/WLS, Wnt secretion, and Wnt activation of β-catenin reporter activity. In mice, C59 displayed good bioavailability, as once daily oral administration was sufficient to maintain blood concentrations well above the IC(50). C59 blocked progression of mammary tumors in MMTV-WNT1 transgenic mice while downregulating Wnt/β-catenin target genes. Surprisingly, mice exhibit no apparent toxicity, such that at a therapeutically effective dose there were no pathologic changes in the gut or other tissues. These results offer preclinical proof-of-concept that inhibiting mammalian Wnts can be achieved by targeting PORCN with small-molecule inhibitors such as C59, and that this is a safe and feasible strategy in vivo.
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Kyle David
authors.initials: KD
authors.lastname: Proffitt
authors.forename: Babita
authors.initials: B
authors.lastname: Madan
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Ke
authors.forename: Vishal
authors.initials: V
authors.lastname: Pendharkar
authors.forename: Lijun
authors.initials: L
authors.lastname: Ding
authors.forename: May Ann
authors.initials: MA
authors.lastname: Lee
authors.forename: Rami N
authors.initials: RN
authors.lastname: Hannoush
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
mesh_terms: D000217:Acyltransferases; D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D011725:Pyridines / Q000494:pharmacology*; D051153:Wnt Proteins; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C579131:2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide; D044482:Benzeneacetamides; D008565:Membrane Proteins; D011725:Pyridines; D051153:Wnt Proteins; D051176:beta Catenin; D000217:Acyltransferases; C491188:PORCN protein, human