Discovery and Optimization of a Porcupine Inhibitor Athisayamani Jeyaraj Duraiswamy, May Ann Lee, Babita Madan, Shi Hua Ang, Eldwin Sum Wai Tan, Wei Wen Vivien Cheong, Zhiyuan Ke, Vishal Pendharkar, Li Jun Ding, Yun Shan Chew, Vithya Manoharan, Kanda Sangthongpitag, Jenefer Alam, Anders Poulsen, Soo Yei Ho, David M Virshup, and Thomas H. Keller Journal of Medicinal Chemistry Just Accepted Manuscript 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, 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.