Exploration of the linkage elements of porcupine antagonists led to potent Wnt signaling pathway inhibitors

被引：19

作者：

Dong, Yan ^{[1
]}

Li, Kehuang ^{[1
]}

Xu, Zhixiang ^{[1
]}

Ma, Haikuo ^{[1
]}

Zheng, Jiyue ^{[1
]}

Hu, Zhilin ^{[2
,3
]}

He, Sudan ^{[2
,3
]}

Wu, Yiyuan ^{[4
]}

Sun, Zhijian ^{[4
]}

Luo, Lusong ^{[4
]}

Li, Jiajun ^{[1
]}

Zhang, Hongjian ^{[1
]}

Zhang, Xiaohu ^{[1
]}

机构：

[1] Soothow Univ, Jiangsu Key Lab Translat Res & Therapy Neuropsych, Suzhou 215021, Jiangsu, Peoples R China

[2] Soochow Univ, Cyrus Tang Hematol Ctr, Jiangsu Inst Hematol, Affiliated Hosp 1, Suzhou 215123, Peoples R China

[3] Soochow Univ, Collaborat Innovat Ctr Hematol, Suzhou 215123, Peoples R China

[4] BeiGene Beijing Co Ltd, Beijing 102206, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2015年 / 23卷 / 21期

基金：

中国国家自然科学基金;

关键词：

Wnt signaling pathway; Porcupine; Antagonist; Scaffold hybridization; Cancer therapy; SMOOTHENED ANTAGONISTS; CANCER; PHARMACOPHORE; OPTIMIZATION; DISCOVERY; RECEPTOR; DESIGN;

D O I：

10.1016/j.bmc.2015.09.048

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The Wnt signaling pathway is a pivotal developmental pathway. It operates through control of cellular functions such as proliferation, differentiation, migration and polarity. Aberrant Wnt signaling has been implicated in the formation and metastasis of tumors. Porcupine is a component of the Wnt signaling pathway. It is a member of the membrane-bound O-acyltransferase family of proteins. Porcupine catalyzes the palmitoylation of Wnt proteins, a process which is essential to their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from two known porcupine inhibitor classes. The leading compound 62 demonstrated subnanomolar (IC50 0.11 nM) inhibition of Wnt signaling in a paracrine cellular reporter gene assay. Compound 62 also potently inhibited Wnt secretion into culture medium, an indication of direct inhibition of the porcupine protein. Furthermore, compound 62 showed excellent chemical, plasma and liver microsomal stabilities. Collectively, these results strongly support further optimization of this novel scaffold to develop better Wnt pathway inhibitors. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：6855 / 6868

页数：14

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