ABSTRACT. Porcupine is an o-acetyl transferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which regulates cell proliferation, migration, stem cell self-renewal and differentiation. This pathway is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics with two compounds undergoing clinical trials. A high throughput screen against porcupine revealed several structurally different potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. The pharmacophore requirements for porcupine inhibitors were elucidated and a pharmacophore model was developed [1]. Our compounds as well as all published porcupine inhibitors may be fitted to this model in low energy conformations with good superimposition of the pharmacophore elements. We then used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping with the aim of getting a backup to our clinical candidate belonging to a different class. The resulting Phtalimide [2] and Maleimide [3] scaffolds were optimized to sub-nanomolar potency while retaining good drug-like properties. The two scaffolds have parallel SAR but the phtalimides are more potent while the maleimides have better physical properties. A pre-clinical development candidate was selected for which extensive in vitro and in vivo profiling is reported. [1] Poulsen, A.; Ho, S. Y.; Wang, W.; Alam, J.; Jeyaraj, D. A.; Ang, S. H.; Tan, E. S.; Lin, G. R.; Cheong, V. W.; Ke, Z.; Lee, M. A.; Keller, T. H., Pharmacophore Model for Wnt/Porcupine Inhibitors and Its Use in Drug Design. J. Chem. Inf. Model. 2015. [2] Wang, W. L.; Ho, S. Y.; Alam, J.; Poulsen, A.; Duraiswamy, J. Phthalimide derivatives as modulators of WNT pathway. GB1409783.6, 2014. [3] Alam, J.; Poulsen, A.; Ho, S. Y.; Wang, W. L.; Duraiswamy, A. J. Maleimide Derivatives as Modulators of WNT Pathway. PCT/SG2014/000601, 2014.

Scaffold hopping and optimization of maleimide based porcupine inhibitors

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.