5 years ago

Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors

Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors
Li Jun Ding, Zhiyuan Ke, May Ann Lee, Vishal Pendharkar, Shi Hua Ang, Duraiswamy Athisayamani Jeyaraj, Jenefer Alam, Thomas H. Keller, Kanda Sangthongpitag, Soo Yei Ho, Eldwin Sum Wai Tan, Yun Shan Chew, Jeffrey Hill, Choon Bing Low, David M. Virshup, Anders Poulsen, Vithya Manoharan, Babita Madan, Weiling Wang, Grace Ruiting Lin
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00662

DOI: 10.1021/acs.jmedchem.7b00662

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