2. Academic Validation
  3. Design, synthesis, and evaluation of novel CXCR4 antagonists based on an aminoquinoline template

Design, synthesis, and evaluation of novel CXCR4 antagonists based on an aminoquinoline template

  • Bioorg Chem. 2020 Jun;99:103824. doi: 10.1016/j.bioorg.2020.103824.
Yu Lin 1,  Zhanhui Li 1,  Chen Xu 1,  Kaijiang Xia 1,  Shuwei Wu 1,  Yongjin Hao 1,  Qing Yang 1,  Haikuo Ma 1,  Jiyue Zheng 2,  Lusong Luo 3,  Fang Zhu 4,  Sudan He 5,  Xiaohu Zhang 6
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China.
  • 2 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China. Electronic address: [email protected].
  • 3 BeiGene (Beijing) Co., Ltd., No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, PR China.
  • 4 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.
  • 5 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].
  • 6 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, PR China. Electronic address: [email protected].
PMID: 32334192 DOI: 10.1016/j.bioorg.2020.103824
Abstract

The Chemokine Receptor CXCR4 has been explored as a drug target due to its involvement in pathological conditions such as HIV Infection and Cancer metastasis. Here we report the structure-activity relationship study of novel CXCR4 antagonists based on an aminoquinoline template. This template is devoid of the chiral center in the classical tetrahydroquinoline (THQ) ring moiety and therefore can be easily synthesized. A number of potent CXCR4 antagonists were identified, exemplified by compound 3, which demonstrated excellent binding affinity with CXCR4 receptor (IC50 = 57 nM) and inhibited CXCL12 induced cytosolic calcium increase (IC50 = 0.24 nM). Furthermore, compound 3 potently inhibited CXLC12/CXCR4 mediated cell migration in a transwell invasion assay. The simplified synthetic approach combined with good physicochemical properties (e.g. MW 362, clogP 2.1, PSA 48, PKA 7.0 for compound 3) demonstrate the potential of this aminoquinoline template as a novel scaffold to develop CXCR4 antagonists.

Keywords

Aminoquinoline; Antagonist; CXCL12; CXCR4; Chemokine; GPCR.

Figures
Products