PMID- 36858339 OWN - NLM STAT- MEDLINE DCOM- 20230323 LR - 20230323 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 945 DP - 2023 Apr 15 TI - Novel PORCN inhibitor WHN-88 targets Wnt/beta-catenin pathway and prevents the growth of Wnt-driven cancers. PG - 175628 LID - S0014-2999(23)00139-5 [pii] LID - 10.1016/j.ejphar.2023.175628 [doi] AB - Wnt/beta-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/beta-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. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Yang, Qihong AU - Yang Q AD - 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. FAU - Qin, Tong AU - Qin T AD - 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. FAU - An, Tao AU - An T AD - 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. FAU - Wu, Hongna AU - Wu H AD - 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. FAU - Xu, Gang AU - Xu G AD - Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, 650091, China. FAU - Xiang, Jin AU - Xiang J AD - State Key Laboratory of Functions and Applications of Medicinal Plants/School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550025, China. FAU - Lei, Kangfan AU - Lei K AD - 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. FAU - Zhang, Shaohua AU - Zhang S AD - Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, 650091, China. FAU - Xia, Jie AU - Xia J AD - 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. FAU - Su, Guifeng AU - Su G AD - 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. FAU - Wang, Dan AU - Wang D AD - Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, 650091, China. FAU - Xue, Minggao AU - Xue M AD - Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, School of Pharmacy, Yunnan University, Kunming, 650091, China. FAU - Kong, Lingmei AU - Kong L AD - 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. FAU - Zhang, Wenxuan AU - Zhang W AD - 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. FAU - Wu, Song AU - Wu S AD - 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. FAU - Li, Yan AU - Li Y AD - 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. LA - eng PT - Journal Article DEP - 20230228 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - EC 2.3.- (Acyltransferases) RN - 0 (beta Catenin) RN - 0 (Ligands) RN - 0 (Membrane Proteins) RN - EC 2.3.1.- (PORCN protein, human) RN - EC 2.3.1.- (Porcn protein, mouse) SB - IM MH - Animals MH - Humans MH - Mice MH - Acyltransferases/chemistry/genetics/metabolism MH - beta Catenin/metabolism MH - Ligands MH - Membrane Proteins/metabolism MH - Mutation MH - *Pancreatic Neoplasms MH - *Wnt Signaling Pathway OTO - NOTNLM OT - PORCN inhibitor OT - Palmitoylation OT - WHN-88 OT - Wnt-driven cancers COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/03/02 06:00 MHDA- 2023/03/22 06:00 CRDT- 2023/03/01 19:27 PHST- 2023/01/09 00:00 [received] PHST- 2023/02/25 00:00 [revised] PHST- 2023/02/27 00:00 [accepted] PHST- 2023/03/02 06:00 [pubmed] PHST- 2023/03/22 06:00 [medline] PHST- 2023/03/01 19:27 [entrez] AID - S0014-2999(23)00139-5 [pii] AID - 10.1016/j.ejphar.2023.175628 [doi] PST - ppublish SO - Eur J Pharmacol. 2023 Apr 15;945:175628. doi: 10.1016/j.ejphar.2023.175628. Epub 2023 Feb 28.