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
  • 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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