2. Academic Validation
  3. Structural optimization of aminopyrimidine-based CXCR4 antagonists

Structural optimization of aminopyrimidine-based CXCR4 antagonists

  • Eur J Med Chem. 2020 Feb 1;187:111914. doi: 10.1016/j.ejmech.2019.111914.
Fang Zhu 1,  Yujie Wang 2,  Qian Du 1,  Wenxiang Ge 3,  Zhanhui Li 2,  Xu Wang 2,  Chunyan Fu 4,  Lusong Luo 4,  Sheng Tian 2,  Haikuo Ma 5,  Jiyue Zheng 6,  Yi Zhang 2,  Xiaotian Sun 7,  Sudan He 8,  Xiaohu Zhang 9
Affiliations

Affiliations

  • 1 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215123, PR China; Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, PR China.
  • 2 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China.
  • 3 Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, PR China; School of Pharmacy, Xi'an Jiaotong University, Xi'an, 710061, PR China.
  • 4 BeiGene (Beijing) Co., Ltd, No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, PR China.
  • 5 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China; Cyrus Tang Hematology Center, Jiangsu Institute of Hematology and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215123, PR China.
  • 6 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China. Electronic address: [email protected].
  • 7 College of Chemistry and Chemical Engineering, And Henan Key Laboratory of Function-Oriented Porous Materials, Luoyang Normal University, Luoyang, 471934, PR China.
  • 8 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215123, PR China; Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medial College, Beijing, Suzhou Institute of Systems Medicine, Suzhou, 215123, Jiangsu, PR China. Electronic address: [email protected].
  • 9 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China. Electronic address: [email protected].
PMID: 31806538 DOI: 10.1016/j.ejmech.2019.111914
Abstract

Structural optimization of aminopyrimidine-based CXCR4 antagonists is reported. The optimization is guided by molecular docking studies based on available CXCR4-small molecule crystal complex. The optimization identifies a number of compounds with improved receptor binding affinity and functional activity exemplified by compound 23 (inhibition of APC-conjugate clone 12G5 for CXCR4 binding in a cell based assay: IC50 = 8.8 nM; inhibition of CXCL12 induced cytosolic calcium increase: IC50 = 0.02 nM). In addition, compound 23 potently inhibits CXCR4/CXLC12 mediated chemotaxis in a matrigel invasion assay. Furthermore, compound 23 exhibits good physicochemical properties (MW 367, clogP 2.1, PSA 48, PKA 7.2) and in vitro safety profiles (marginal/moderate inhibition of CYP isozymes and hERG). These results represent significant improvement over the initial hit from scaffold hybridization and suggest that compound 23 can be used as a starting point to support lead optimization.

Keywords

Antagonist; CXCR4; Chemokine; GPCR; Structural optimization.

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