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Author Notes:

Corresponding author. Hyunsuk Shim, Department of Radiation Oncology, Emory University School of Medicine; phone, 404-778-4564; fax, 404-712-5813; hshim@emory.edu; address, 1701 Uppergate Drive, C5018, Atlanta, GA 30322.

We thank Ms. Jessica Paulishen for proof-reading.


Research Funding:

This study was financially supported by a research grant from NIH NCI (R01 CA165306).

C.C.Y. was supported by VA Merit Award BX002540.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Chemistry, Medicinal
  • Pharmacology & Pharmacy
  • CXCR4
  • Amide-sulfamide
  • Virtual HTS
  • Compound library building
  • Anti-inflammatory activity
  • AKT

Development of CXCR4 modulators by virtual HTS of a novel amidesulfamide compound library


Journal Title:

European Journal of Medicinal Chemistry


Volume 126


, Pages 464-475

Type of Work:

Article | Post-print: After Peer Review


CXCR4 plays a crucial role in recruitment of inflammatory cells to inflammation sites at the beginning of the disease process. Modulating CXCR4 functions presents a new avenue for anti-inflammatory strategies. However, using CXCR4 antagonists for a long term usage presents potential serious side effect due to their stem cell mobilizing property. We have been developing partial CXCR4 antagonists without such property. A new computer-aided drug design program, the FRESH workflow, was used for anti-CXCR4 lead compound discovery and optimization, which coupled both compound library building and CXCR4 docking screens in one campaign. Based on the designed parent framework, 30 prioritized amide-sulfamide structures were obtained after systemic filtering and docking screening. Twelve compounds were prepared from the top-30 list. Most synthesized compounds exhibited good to excellent binding affinity to CXCR4. Compounds Ig and Im demonstrated notable in vivo suppressive activity against xylene-induced mouse ear inflammation (with 56% and 54% inhibition). Western blot analyses revealed that Ig significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, Ig attenuated the amount of TNF-α secreted by pathogenic E. coli-infected macrophages. More importantly, Ig had no observable cytotoxicity. Our results demonstrated that FRESH virtual high throughput screening program of targeted chemical class could successfully find potent lead compounds, and the amide-sulfamide pharmacophore was a novel and effective framework blocking CXCR4 function.

Copyright information:

© 2016 Elsevier Masson SAS. All rights reserved.

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