2. Academic Validation
  3. Novel PORCN inhibitor WHN-88 targets Wnt/β-catenin pathway and prevents the growth of Wnt-driven cancers

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

  • Eur J Pharmacol. 2023 Feb 27;175628. doi: 10.1016/j.ejphar.2023.175628.
Qihong Yang 1,  Tong Qin 2,  Tao An 3,  Hongna Wu 2,  Gang Xu 4,  Jin Xiang 5,  Kangfan Lei 2,  Shaohua Zhang 4,  Jie Xia 2,  Guifeng Su 6,  Dan Wang 4,  Minggao Xue 4,  Lingmei Kong 6,  Wenxuan Zhang 7,  Song Wu 8,  Yan Li 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China.
  • 3 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, Shandong, China.
  • 4 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, 650091, China.
  • 5 State Key Laboratory of Functions and Applications of Medicinal Plants/School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, China.
  • 6 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, 650091, China.
  • 7 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China. Electronic address: wxzhang@imm.ac.cn.
  • 8 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, China. Electronic address: ws@imm.ac.cn.
  • 9 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China; Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, 650091, China. Electronic address: yan.li@ynu.edu.cn.
PMID: 36858339 DOI: 10.1016/j.ejphar.2023.175628
Abstract

Wnt/β-catenin signaling pathway is a classical and crucial oncogenic pathway in many carcinomas, and Porcupine (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/β-catenin signaling transduction. Further experiments showed that, at well-tolerated doses, WHN-88 remarkably suppressed 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 teratocarcinoma 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.

Keywords

PORCN inhibitor; Palmitoylation; WHN-88; Wnt-driven cancers.

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