2. Academic Validation
  3. Design, synthesis, and evaluation of novel porcupine inhibitors featuring a fused 3-ring system based on the 'reversed' amide scaffold

Design, synthesis, and evaluation of novel porcupine inhibitors featuring a fused 3-ring system based on the 'reversed' amide scaffold

  • Bioorg Med Chem. 2016 Nov 15;24(22):5861-5872. doi: 10.1016/j.bmc.2016.09.041.
Zhixiang Xu 1,  Xiangxiang Xu 1,  Ruadhan O'Laoi 2,  Haikuo Ma 1,  Jiyue Zheng 3,  Shuaishuai Chen 4,  Lusong Luo 5,  Zhilin Hu 6,  Sudan He 6,  Jiajun Li 1,  Hongjian Zhang 1,  Xiaohu Zhang 7
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China.
  • 2 Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
  • 3 Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China. Electronic address: [email protected].
  • 4 BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China.
  • 5 BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China. Electronic address: [email protected].
  • 6 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital, and Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215123, PR China.
  • 7 Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psychiatric-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215021, PR China. Electronic address: [email protected].
PMID: 27692509 DOI: 10.1016/j.bmc.2016.09.041
Abstract

The Wnt signaling pathway is an essential signal transduction pathway which leads to the regulation of cellular processes such as proliferation, differentiation and migration. Aberrant Wnt signaling is known to have an association with multiple cancers. Porcupine is an Enzyme that catalyses the addition of palmitoleate to a serine residue in Wnt proteins, a process which is required for the secretion of Wnt proteins. Here we report the synthesis and structure-activity-relationship of the novel Porcupine inhibitors based on a 'reversed' amide scaffold. The leading compound 53 was as potent as the clinical compound LGK974 in a cell based STF reporter gene assay. Compound 53 potently inhibited the secretion of Wnt3A, therefore was confirmed to be a Porcupine Inhibitor. Furthermore, compound 53 showed excellent chemical and plasma stabilities. However, the clearance of compound 53 in liver microsomal tests was moderate to high, and the solubility of compound 53 was suboptimal. Collective efforts toward further optimization of this novel tricyclic template to develop better Porcupine inhibitors will be subsequently undertaken and reported in due course.

Keywords

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

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