Novel PORCN inhibitor WHN-88 targets Wnt/?-catenin pathway and prevents the growth of Wnt-driven cancers

doi:10.1016/j.ejphar.2023.175628

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	Novel PORCN inhibitor WHN-88 targets Wnt/?-catenin pathway and prevents the growth of Wnt-driven cancers
	Yang,Qihong; Qin,Tong; An,Tao; Wu,Hongna; Xu,Gang; Xiang,Jin; Lei,Kangfan; Zhang,Shaohua; Xia,Jie; Su,Guifeng; Wang,Dan; Xue,Minggao; Kong,Lingmei; Zhang,Wenxuan; Wu,Song; Li,Yan
	2023
发表期刊	EUROPEAN JOURNAL OF PHARMACOLOGY
ISSN	1879-0712
卷号	945 页码:175628
摘要	Wnt/13-catenin signaling pathway is a classical and crucial oncogenic pathway in many carcinomas, and Por-cupine (PORCN) is an O-acyltransferase, which is indispensable and highly specific for catalyzing palmitoylation of Wnt ligands and facilitating their secretion and biofunction. Targeting PORCN provides a promising approach to specifically cure Wnt-driven cancers from the root. In this study, we designed series of pyridonyl acetamide compounds, and discovered a novel PORCN inhibitor WHN-88 with a unique di-iodinated pyridone structural fragment, which is significantly different from the reported inhibitors. We demonstrated that WHN-88 effectively abolished palmitoylation of Wnt ligands and prevented their secretion and the subsequent Wnt/13-catenin signaling transduction. Further experiments showed that, at well-tolerated doses, WHN-88 remarkably sup-pressed the spontaneous occurrence and growth of MMTV-Wnt1 murine breast tumors. Consistently, WHN-88 also notably restrained the progress of xenografted Wnt-driven human tumors, including PA-1 teratocarci-noma with high autocrine Wnt signaling and Aspc-1 pancreatic carcinoma with Wnt-sensitizing RNF43 mutation. Additionally, we disclosed that WHN-88 inhibited cancer cell stemness obviously. Together, we verified WHN-88 is a novel PORCN inhibitor with potent efficacy against the Wnt-driven cancers. Our findings enriched the structural types of PORCN inhibitors, and facilitated the development and application of PORCN inhibiting therapy in clinic.
关键词	PORCN inhibitor WHN-88 Palmitoylation Wnt-driven cancers SIGNALING PATHWAY PORCUPINE STEM GENE ACYLTRANSFERASE MUTATIONS POLARITY PROTEIN RNF43 MICE
学科领域	Pharmacology & Pharmacy
DOI	10.1016/j.ejphar.2023.175628
收录类别	SCI
WOS记录号	WOS:000953129000001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75585
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Yang,Qihong,Qin,Tong,An,Tao,et al. Novel PORCN inhibitor WHN-88 targets Wnt/?-catenin pathway and prevents the growth of Wnt-driven cancers[J]. EUROPEAN JOURNAL OF PHARMACOLOGY,2023,945:175628.
APA	Yang,Qihong.,Qin,Tong.,An,Tao.,Wu,Hongna.,Xu,Gang.,...&Li,Yan.(2023).Novel PORCN inhibitor WHN-88 targets Wnt/?-catenin pathway and prevents the growth of Wnt-driven cancers.EUROPEAN JOURNAL OF PHARMACOLOGY,945,175628.
MLA	Yang,Qihong,et al."Novel PORCN inhibitor WHN-88 targets Wnt/?-catenin pathway and prevents the growth of Wnt-driven cancers".EUROPEAN JOURNAL OF PHARMACOLOGY 945(2023):175628.

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