Exploration of the linkage elements of porcupine antagonists led to potent Wnt signaling pathway inhibitors. Issue 21 (1st November 2015)

• Record Type: Journal Article
• Authors: Dong, Yan; Li, Kehuang; Xu, Zhixiang; Ma, Haikuo; Zheng, Jiyue; Hu, Zhilin; He, Sudan; Wu, Yiyuan; Sun, Zhijian; Luo, Lusong; Li, Jiajun; Zhang, Hongjian; Zhang, Xiaohu
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 21(2015)
• Page Start: 6855
• Page End: 6868
• Publication Date: 2015-11-01
• Subjects: 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–activity relationship -- SEM standard error measurement -- SGF simulated gastric fluid -- sHh sonic hedgehog -- Smo smoothened -- STF super-top flash; Wnt signaling pathway -- Porcupine -- Antagonist -- Scaffold hybridization -- Cancer therapy; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.09.048
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 compound62 demonstrated subnanomolar (IC50 0.11 nM) inhibition of Wnt signaling in a paracrine cellular reporter gene assay. Compound62 also potently inhibited Wnt secretion into culture medium, an indication of direct inhibition of the porcupine protein. Furthermore, compound62 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.