title: Design, synthesis, and evaluation of potent Wnt signaling inhibitors featuring a fused 3-ring system.
abstract: The Wnt signaling pathway is a critical developmental pathway which operates through control of cellular functions such as proliferation and differentiation. Aberrant Wnt signaling has been linked to the formation and metastasis of tumors. Porcupine, a member of the membrane-bound O-acyltransferase family of proteins, is an important component of the Wnt pathway. Porcupine catalyzes the palmitoylation of Wnt proteins, a process needed for their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from a known porcupine inhibitor class. The leading compound 59 demonstrated subnanomolar inhibition of Wnt signaling in a paracrine cellular assay. Compound 59 also showed excellent chemical, plasma and liver microsomal stabilities. Furthermore, compound 59 exhibited good pharmacokinetic profiles with 30% oral bioavailability in rat. 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: 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: Jiajun
authors.initials: J
authors.lastname: Li
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: 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: 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: 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; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D051153:Wnt Proteins; D000217:Acyltransferases; C491188:PORCN protein, human
keywords: Antagonist; Cancer therapy; Porcupine; Scaffold hybridization; Wnt signaling pathway