title: Discovery and Optimization of a Porcupine Inhibitor.
abstract: 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.
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Athisayamani Jeyaraj
authors.initials: AJ
authors.lastname: Duraiswamy
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: May Ann
authors.initials: MA
authors.lastname: Lee
authors.affiliation: ‡Duke-NUS Graduate Medical School Singapore, 8 College Road, 169857, Singapore.
authors.forename: Babita
authors.initials: B
authors.lastname: Madan
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Shi Hua
authors.initials: SH
authors.lastname: Ang
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Eldwin Sum Wai
authors.initials: ES
authors.lastname: Tan
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Wei Wen Vivien
authors.initials: WW
authors.lastname: Cheong
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Ke
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Vishal
authors.initials: V
authors.lastname: Pendharkar
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Li Jun
authors.initials: LJ
authors.lastname: Ding
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Yun Shan
authors.initials: YS
authors.lastname: Chew
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Vithya
authors.initials: V
authors.lastname: Manoharan
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Jenefer
authors.initials: J
authors.lastname: Alam
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Soo Yei
authors.initials: SY
authors.lastname: Ho
authors.affiliation: ‡Duke-NUS Graduate Medical School Singapore, 8 College Road, 169857, Singapore.
authors.forename: David M
authors.initials: DM
authors.lastname: Virshup
authors.affiliation: †Experimental Therapeutics Centre, 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
mesh_terms: D000217:Acyltransferases; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D060449:Wnt Signaling Pathway
chemical_list: D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D000217:Acyltransferases; C491188:PORCN protein, human