PMID- 26110200
OWN - NLM
STAT- MEDLINE
DCOM- 20151208
LR  - 20171116
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 58
IP  - 15
DP  - 2015 Aug 13
TI  - Discovery and Optimization of a Porcupine Inhibitor.
PG  - 5889-99
LID - 10.1021/acs.jmedchem.5b00507 [doi]
AB  - 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.
FAU - Duraiswamy, Athisayamani Jeyaraj
AU  - Duraiswamy AJ
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Lee, May Ann
AU  - Lee MA
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Madan, Babita
AU  - Madan B
AD  - double daggerDuke-NUS Graduate Medical School Singapore, 8 College Road, 169857, Singapore.
FAU - Ang, Shi Hua
AU  - Ang SH
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Tan, Eldwin Sum Wai
AU  - Tan ES
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Cheong, Wei Wen Vivien
AU  - Cheong WW
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Ke, Zhiyuan
AU  - Ke Z
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Pendharkar, Vishal
AU  - Pendharkar V
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Ding, Li Jun
AU  - Ding LJ
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Chew, Yun Shan
AU  - Chew YS
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Manoharan, Vithya
AU  - Manoharan V
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Sangthongpitag, Kanda
AU  - Sangthongpitag K
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Alam, Jenefer
AU  - Alam J
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Poulsen, Anders
AU  - Poulsen A
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Ho, Soo Yei
AU  - Ho SY
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
FAU - Virshup, David M
AU  - Virshup DM
AD  - double daggerDuke-NUS Graduate Medical School Singapore, 8 College Road, 169857, Singapore.
FAU - Keller, Thomas H
AU  - Keller TH
AD  - daggerExperimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, 
      Singapore.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150716
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Membrane Proteins)
RN  - EC 2.3.- (Acyltransferases)
RN  - EC 2.3.1.- (PORCN protein, human)
SB  - IM
MH  - Acyltransferases
MH  - Drug Discovery
MH  - Enzyme Inhibitors/chemistry/*pharmacology
MH  - Membrane Proteins/*antagonists & inhibitors
MH  - Models, Molecular
MH  - Structure-Activity Relationship
MH  - Wnt Signaling Pathway
EDAT- 2015/06/26 06:00
MHDA- 2015/12/15 06:00
CRDT- 2015/06/26 06:00
PHST- 2015/06/26 06:00 [entrez]
PHST- 2015/06/26 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
AID - 10.1021/acs.jmedchem.5b00507 [doi]
PST - ppublish
SO  - J Med Chem. 2015 Aug 13;58(15):5889-99. doi: 10.1021/acs.jmedchem.5b00507. Epub 
      2015 Jul 16.