Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors.

Journal Article (Journal Article)

Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics. A high throughput screen against porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. We developed a pharmacophore model and used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping. The resulting maleimide scaffold was optimized to subnanomolar potency while retaining good physical druglike properties. A preclinical development candidate was selected for which extensive in vitro and in vivo profiling is reported.

Full Text

Duke Authors

Cited Authors

  • Ho, SY; Alam, J; Jeyaraj, DA; Wang, W; Lin, GR; Ang, SH; Tan, ESW; Lee, MA; Ke, Z; Madan, B; Virshup, DM; Ding, LJ; Manoharan, V; Chew, YS; Low, CB; Pendharkar, V; Sangthongpitag, K; Hill, J; Keller, TH; Poulsen, A

Published Date

  • August 10, 2017

Published In

Volume / Issue

  • 60 / 15

Start / End Page

  • 6678 - 6692

PubMed ID

  • 28671458

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/acs.jmedchem.7b00662


  • eng

Conference Location

  • United States