Discovery and Optimization Of a Porcupine Inhibitor

被引：36

作者：

Duraiswamy, Athisayamani Jeyaraj ^{[1
]}

Lee, May Ann ^{[1
]}

Madan, Babita ^{[2
]}

Ang, Shi Hua ^{[1
]}

Tan, Eldwin Sum Wai ^{[1
]}

Cheong, Wei Wen Vivien ^{[1
]}

Ke, Zhiyuan ^{[1
]}

Pendharkar, Vishal ^{[1
]}

Ding, Li Jun ^{[1
]}

Chew, Yun Shan ^{[1
]}

Manoharan, Vithya ^{[1
]}

Sangthongpitag, Kanda ^{[1
]}

Alam, Jenefer ^{[1
]}

Poulsen, Anders ^{[1
]}

Ho, Soo Yei ^{[1
]}

Virshup, David M. ^{[2
]}

Keller, Thomas H. ^{[1
]}

机构：

[1] Ctr Expt Therapeut, Singapore 138669, Singapore

[2] Duke NUS Grad Med Sch Singapore, Singapore 169857, Singapore

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 15期

基金：

英国医学研究理事会; 新加坡国家研究基金会;

关键词：

WNT; PATHWAY; SECRETION; GROWTH; SIGNAL;

D O I：

10.1021/acs.jmedchem.5b00507

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 bioavallability 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.

引用

页码：5889 / 5899

页数：11

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