PMID- 23188502
OWN - NLM
STAT- MEDLINE
DCOM- 20130326
LR  - 20230108
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 73
IP  - 2
DP  - 2013 Jan 15
TI  - Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of 
      WNT-driven mammary cancer.
PG  - 502-7
LID - 10.1158/0008-5472.CAN-12-2258 [doi]
AB  - 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 beta-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/beta-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.
FAU - Proffitt, Kyle David
AU  - Proffitt KD
AD  - Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, 
      Singapore, Singapore.
FAU - Madan, Babita
AU  - Madan B
FAU - Ke, Zhiyuan
AU  - Ke Z
FAU - Pendharkar, Vishal
AU  - Pendharkar V
FAU - Ding, Lijun
AU  - Ding L
FAU - Lee, May Ann
AU  - Lee MA
FAU - Hannoush, Rami N
AU  - Hannoush RN
FAU - Virshup, David M
AU  - Virshup DM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121127
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide)
RN  - 0 (Benzeneacetamides)
RN  - 0 (Membrane Proteins)
RN  - 0 (Pyridines)
RN  - 0 (Wnt Proteins)
RN  - 0 (beta Catenin)
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 2.3.1.- (PORCN protein, human)
SB  - IM
MH  - Acyltransferases
MH  - Animals
MH  - Benzeneacetamides/*pharmacology
MH  - Breast Neoplasms/*enzymology/pathology
MH  - Cell Line, Tumor
MH  - Humans
MH  - Membrane Proteins/*antagonists & inhibitors
MH  - Mice
MH  - Pyridines/*pharmacology
MH  - *Wnt Proteins
MH  - Wnt Signaling Pathway
MH  - beta Catenin/metabolism
EDAT- 2012/11/29 06:00
MHDA- 2013/03/27 06:00
CRDT- 2012/11/29 06:00
PHST- 2012/11/29 06:00 [entrez]
PHST- 2012/11/29 06:00 [pubmed]
PHST- 2013/03/27 06:00 [medline]
AID - 0008-5472.CAN-12-2258 [pii]
AID - 10.1158/0008-5472.CAN-12-2258 [doi]
PST - ppublish
SO  - Cancer Res. 2013 Jan 15;73(2):502-7. doi: 10.1158/0008-5472.CAN-12-2258. Epub 
      2012 Nov 27.