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 b-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/b-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. Cancer Res; 73(2); 502-7. Ó2012 AACR.

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

“…Consistent with this, tankyrase inhibitors demonstrated severe, mechanism-based GI toxicity when given orally (14). In contrast with tankyrase inhibitors, PORCN inhibitors and the recombinant Frizzled inhibitory antibodies have not shown significant toxic effects on the intestine or skin, at least in mice, at doses that effectively inhibit cancer proliferation (30,34,37). Doses of the PORCN inhibitor Wnt C-59 10-fold higher than the therapeutic dose cause extensive loss of intestinal proliferation (37).…”

Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974

“…9,13,22 A crucial component necessary for Wnt ligand transport, secretion, and activity is PORCN, which has been identified as a potential target to inhibit Wnt/β-catenin signaling. 15 Wnt pathway inhibitor success has been limited because of a narrow therapeutic window for activity since normal tissue stability requires Wnt/β-catenin signaling and a lack of predictive biomarkers of response. WNT974 inhibits Wnt/β-catenin signaling through inhibition of the PORCN enzyme, which causes a decrease in secretion of Wnt ligands.…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…It is therefore not surprising that so much effort has gone into the development of new drugs based on our knowledge of Wnt signaling to treat disease. Among the commercially available drugs that have been developed to manipulate Wnt signaling are IWP-2 and Wnt-C59, potent porcupine inhibitors that block Wnt secretion [13,14], IWR-1 and XAV939, which are tankyrase inhibitors that stabilize Axin and thereby inhibiting canonical Wnt signaling [13,15], CHIR99021 (CHIR), a GSK-3 inhibitor that activates Wnt signaling [16], and iCRT-14, which inhibits the β-catenin/TCF complex [17]. These inhibitors, as well as several others not mentioned here, have been important for driving progress of research in this field, and the development of possible therapies for Wnt-related diseases.…”