A Pharmacophore Model for Wnt/Porcupine Inhibitors and its Use for Drug Design

A Pharmacophore Model for Wnt/Porcupine Inhibitors and its Use for Drug Design
Title:
A Pharmacophore Model for Wnt/Porcupine Inhibitors and its Use for Drug Design
Other Titles:
Journal of Chemical Information and Modeling
Publication Date:
29 May 2015
Citation:
A Pharmacophore Model for Wnt/Porcupine Inhibitors and its Use for Drug Design Anders Poulsen, Soo Yei Ho, Weiling Wang, Jenefer Alam, Duraiswamy Athisayamani Jeyaraj, Shi Hua Ang, Eldwin Sum Wai Tan, Grace Ruiting Lin, Vivien Wei Wen Cheong, Zhiyuan Ke, May Ann Lee, and Thomas H. Keller Journal of Chemical Information and Modeling Just Accepted Manuscript DOI: 10.1021/acs.jcim.5b00159
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.
License type:
PublisherCopyrights
Funding Info:
Agency for Science, Technology and Research (A*STAR)
Description:
ISSN:
1549-9596
Files uploaded:

File Size Format Action
poulsen-jciam-2015-101021acsjcim5b00159.pdf 1.35 MB PDF Open