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

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• 作者：Yan Dong^a ; ^&dagger ; ; Kehuang Li^a ; ^&dagger ; ; Zhixiang Xu^a ; Haikuo Ma^a ; Jiyue Zheng^a ; ^{jyzheng@suda.edu.cn" class="auth_mail" title="E-mail the corresponding author} ; Zhilin Hu^b ; Sudan He^b ; Yiyuan Wu^c ; Zhijian Sun^c ; Lusong Luo^c ; ^{lusong.luo@beigene.com" class="auth_mail" title="E-mail the corresponding author} ; Jiajun Li^a ; Hongjian Zhang^a ; Xiaohu Zhang^a ; ^{xiaohuzhang@suda.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CYP ; cytochrome P450 ; DCM ; dichloromethane ; DIPEA ; N ; N-diisopropylethylamine ; DMF ; N ; N-dimethylformamide ; DMSO ; dimethyl sulfoxide ; DSH ; Dishevelled ; HPLC ; high performance liquid chromatography ; mp ; melting point ; N-G-L ; NIH3T3-GRE-Luc reporter gene assay ; PBST ; PBS buffer supplied with 0.05% Tween-20 ; P.K. ; pharmacokinetics ; PPA ; polyphosphoric acid ; PPACA ; propylphosphonic anhydride ; SAR ; structure&ndash ; activity relationship ; SEM ; standard error measurement ; SGF ; simulated gastric fluid ; sHh
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2015
• 出版时间：1 November 2015
• 年：2015
• 卷：23
• 期：21
• 页码：6855-6868
• 全文大小：1311 K

文摘

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 class="boldFont">62 demonstrated subnanomolar (IC₅₀ 0.11 nM) inhibition of Wnt signaling in a paracrine cellular reporter gene assay. Compound class="boldFont">62 also potently inhibited Wnt secretion into culture medium, an indication of direct inhibition of the porcupine protein. Furthermore, compound class="boldFont">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.