title: Exploration of the linkage elements of porcupine antagonists led to potent Wnt signaling pathway inhibitors.
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 compound 62 demonstrated subnanomolar (IC50 0.11 nM) inhibition of Wnt signaling in a paracrine cellular reporter gene assay. Compound 62 also potently inhibited Wnt secretion into culture medium, an indication of direct inhibition of the porcupine protein. Furthermore, compound 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.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China.
authors.forename: Kehuang
authors.initials: K
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China.
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China.
authors.forename: Haikuo
authors.initials: H
authors.lastname: Ma
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China. Electronic address: jyzheng@suda.edu.cn.
authors.forename: Jiyue
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, PR China.
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, PR China.
authors.forename: Sudan
authors.initials: S
authors.lastname: He
authors.affiliation: BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China.
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Sun
authors.affiliation: BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China. Electronic address: lusong.luo@beigene.com.
authors.forename: Lusong
authors.initials: L
authors.lastname: Luo
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China. Electronic address: xiaohuzhang@suda.edu.cn.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000217:Acyltransferases; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D008565:Membrane Proteins; D011719:Pyrazines; D011725:Pyridines; D051544:Cytochrome P-450 CYP3A; D000217:Acyltransferases; C491188:PORCN protein, human; C586458:LGK974
keywords: Antagonist; Cancer therapy; Porcupine; Scaffold hybridization; Wnt signaling pathway