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
  • 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: [email protected].
  • 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: [email protected].
  • 5. Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215123, PR China. Electronic address: [email protected].
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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