Discovery and Optimization of a Porcupine Inhibitor

• Published in: Journal of medicinal chemistry 2015-08, Vol.58 (15), p.5889-5899
• Main Authors: Duraiswamy, Athisayamani Jeyaraj, Lee, May Ann, Madan, Babita, Ang, Shi Hua, Tan, Eldwin Sum Wai, Cheong, Wei Wen Vivien, Ke, Zhiyuan, Pendharkar, Vishal, Ding, Li Jun, Chew, Yun Shan, Manoharan, Vithya, Sangthongpitag, Kanda, Alam, Jenefer, Poulsen, Anders, Ho, Soo Yei, Virshup, David M, Keller, Thomas H
• Format: Article
• Language: English
• Subjects: Acyltransferases; Drug Discovery; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Membrane Proteins - antagonists & inhibitors; Models, Molecular; Structure-Activity Relationship; Wnt Signaling Pathway
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b00507

Wnt proteins regulate various cellular functions and serve distinct roles in normal development throughout life. Wnt signaling is dysregulated in various diseases including cancers. Porcupine (PORCN) is a membrane-bound O-acyltransferase that palmitoleates the Wnts and hence is essential for their secretion and function. The inhibition of PORCN could serve as a therapeutic approach for the treatment of a number of Wnt-dependent cancers. Herein, we describe the identification of a Wnt secretion inhibitor from cellular high throughput screening. Classical SAR based cellular optimization provided us with a PORCN inhibitor with nanomolar activity and excellent bioavailability that demonstrated efficacy in a Wnt-driven murine tumor model. Finally, we also discovered that enantiomeric PORCN inhibitors show very different activity in our reporter assay, suggesting that such compounds may be useful for mode of action studies on the PORCN O-acyltransferase.