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.
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Authors | Zhanhui Li, Xu Wang, Yu Lin, Yujie Wang, Shuwei Wu, Kaijiang Xia, Chen Xu, Haikuo Ma, Jiyue Zheng, Lusong Luo, Fang Zhu, Sudan He, Xiaohu Zhang |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 205
Pg. 112537
(Nov 01 2020)
ISSN: 1768-3254 [Electronic] France |
PMID | 32768738
(Publication Type: Journal Article)
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Copyright | Copyright © 2020 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- Antineoplastic Agents
- CXCR4 protein, human
- Pyrrolidines
- Receptors, CXCR4
- pyrrolidine
- Calcium
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Topics |
- Animals
- Antineoplastic Agents
(chemical synthesis, chemistry, pharmacology)
- Calcium
(metabolism)
- Cell Line, Tumor
- Chemistry Techniques, Synthetic
- Cytosol
(drug effects, metabolism)
- Drug Design
- Humans
- Mice
- Neoplasm Metastasis
- Pyrrolidines
(chemical synthesis, chemistry, pharmacology)
- Rats
- Receptors, CXCR4
(antagonists & inhibitors)
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