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  • Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors.

Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors.

Journal of medicinal chemistry (2017-07-04)
Soo Yei Ho, Jenefer Alam, Duraiswamy Athisayamani Jeyaraj, Weiling Wang, Grace Ruiting Lin, Shi Hua Ang, Eldwin Sum Wai Tan, May Ann Lee, Zhiyuan Ke, Babita Madan, David M Virshup, Li Jun Ding, Vithya Manoharan, Yun Shan Chew, Choon Bing Low, Vishal Pendharkar, Kanda Sangthongpitag, Jeffrey Hill, Thomas H Keller, Anders Poulsen
ABSTRACT

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.

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4-(Thiophen-3-yl)aniline, 97%