2. Academic Validation
  3. Design, synthesis, and evaluation of pyrrolidine based CXCR4 antagonists with in vivo anti-tumor metastatic activity

Design, synthesis, and evaluation of pyrrolidine based CXCR4 antagonists with in vivo anti-tumor metastatic activity

  • Eur J Med Chem. 2020 Nov 1;205:112537. doi: 10.1016/j.ejmech.2020.112537.
Zhanhui Li 1,  Xu Wang 1,  Yu Lin 1,  Yujie Wang 1,  Shuwei Wu 1,  Kaijiang Xia 1,  Chen Xu 1,  Haikuo Ma 1,  Jiyue Zheng 1,  Lusong Luo 2,  Fang Zhu 3,  Sudan He 4,  Xiaohu Zhang 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China.
  • 2 BeiGene (Beijing) Co., Ltd., No. 30 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, PR China. Electronic address: lusong.luo@beigene.com.
  • 3 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.
  • 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. Electronic address: hesudan2018@163.com.
  • 5 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China. Electronic address: xiaohuzhang@suda.edu.cn.
PMID: 32768738 DOI: 10.1016/j.ejmech.2020.112537
Abstract

The Chemokine Receptor CXCR4 has been proposed as a drug target based on its important functions in HIV Infection, inflammation/autoimmune diseases and Cancer metastasis. Herein we report the design, synthesis and evaluation of novel CXCR4 antagonists based on a pyrrolidine scaffold. The structural exploration/optimization identified numerous potent CXCR4 antagonists, represented by compound 46, which displayed potent binding affinity to CXCR4 receptor (IC50 = 79 nM competitively displacing fluorescent 12G5 antibody) and inhibited CXCL12 induced cytosolic calcium flux (IC50 = 0.25 nM). Moreover, in a transwell invasion assay, compound 46 significantly mitigated CXCL12/CXCR4 mediated cell migration. Compound 46 exhibited good physicochemical properties (MW 367, logD7.4 1.12, PKA 8.2) and excellent in vitro safety profiles (e.g., hERG patch clamp IC50 > 30 μM and minimal CYP isozyme inhibition). Importantly, 46 displayed much improved metabolic stability in human and rat liver microsomes. Lastly, 46 demonstrated marked efficacy in a Cancer metastasis model in mice. These results strongly support 46 as a prototypical lead for the development of promising CXCR4 antagonists as clinical candidates.

Keywords

Antagonist; CXCL12; CXCR4; Chemokine; GPCR.

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