2. Academic Validation
  3. Design, synthesis, and evaluation of potent Wnt signaling inhibitors featuring a fused 3-ring system

Design, synthesis, and evaluation of potent Wnt signaling inhibitors featuring a fused 3-ring system

  • Eur J Med Chem. 2016 Jan 27:108:154-165. doi: 10.1016/j.ejmech.2015.11.026.
Zhixiang Xu 1,  Jiajun Li 1,  Yiyuan Wu 2,  Zhijian Sun 2,  Lusong Luo 3,  Zhilin Hu 4,  Sudan He 4,  Jiyue Zheng 5,  Hongjian Zhang 1,  Xiaohu Zhang 6
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China.
  • 2 BeiGene (Beijing) Co., Ltd., No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China.
  • 3 BeiGene (Beijing) Co., Ltd., No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China. Electronic address: lusong.luo@beigene.com.
  • 4 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, PR China.
  • 5 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.
  • 6 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.
PMID: 26647303 DOI: 10.1016/j.ejmech.2015.11.026
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.

Keywords

Antagonist; Cancer therapy; Porcupine; Scaffold hybridization; Wnt signaling pathway.

Figures