title: Pharmacophore Model for Wnt/Porcupine Inhibitors and Its Use in Drug Design.
abstract: Porcupine is a component of the Wnt pathway which regulates cell proliferation, migration, stem cell self-renewal, and differentiation. The Wnt pathway has been shown to be dysregulated in a variety of cancers. Porcupine is a membrane bound O-acyltransferase that palmitoylates Wnt. Inhibiting porcupine blocks the secretion of Wnt and effectively inhibits the Wnt pathway. Using high throughput screening, we have identified a number of novel porcupine inhibitors with diverse scaffolds. The pharmacophore requirements for our porcupine inhibitors were elucidated, and a pharmacophore model is proposed. Our compounds as well as all currently published porcupine inhibitors may be fitted to this model in low energy conformations with good superimposition of the pharmacophore elements. The model also explains the stereochemical requirements of our chiral porcupine inhibitors. The pharmacophore model was successfully used for designing 3 new series of porcupine inhibitors having a tricyclic xantine, a phtalimide, or a piperidine-maleimide scaffold.
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: Soo Yei
authors.initials: SY
authors.lastname: Ho
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: Weiling
authors.initials: W
authors.lastname: Wang
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: Jenefer
authors.initials: J
authors.lastname: Alam
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: Duraiswamy A
authors.initials: DA
authors.lastname: Jeyaraj
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: Shi Hua
authors.initials: SH
authors.lastname: Ang
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: Eldwin Sum Wai
authors.initials: ES
authors.lastname: Tan
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: Grace Ruiting
authors.initials: GR
authors.lastname: Lin
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: Vivien Wei Wen
authors.initials: VW
authors.lastname: Cheong
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Ke
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: May Ann
authors.initials: MA
authors.lastname: Lee
authors.affiliation: Experimental Therapeutics Centre, Agency for Science, Technology and Research, 31 Biopolis Way, Nanos Level 3, Singapore 138669.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
mesh_terms: D000217:Acyltransferases; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D013237:Stereoisomerism; D013379:Substrate Specificity; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*
chemical_list: D008565:Membrane Proteins; D051153:Wnt Proteins; D000217:Acyltransferases; C491188:PORCN protein, human