Abstract |
The C-X-C motif ligand 8 and C-X-C chemokine receptor 2 (CXCL8-CXCR2) axis is involved in pathogenesis of various diseases including inflammation and cancers. Various CXCR2 antagonists are under development for several diseases. Our previous high-throughput cell-based assay specific for CXCR2 has identified a pyrimidine-based compound CX797 acting on CXCR2 down-stream signaling. A lead optimization campaign through scaffold-hopping strategy led to a series of 2-thioureidothiophene-3-carboxylates (TUTP) as novel CXCR2 antagonists. Structure-activity relationship study of TUTPs led to the identification of compound 52 that significantly inhibited CXCR2-mediated β- arrestin recruitment signaling (IC50 = 1.1±0.01 μM) with negligible effect on CXCL8-mediated cAMP signaling and calcium flux. Similar to the known CXCR2 antagonist SB265610, compound 52 inhibited CXCL8-CXCR2 induced phosphorylation of ERK1/2. TUTP compounds also inhibited CXCL8-mediated cell migration and showed synergy with doxorubicin in ovarian cancer cells, thereby supporting TUTPs as promising compounds for cancer treatment.
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Authors | Ding Xue, Wenmin Chen, Nouri Neamati |
Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 204
Pg. 112387
(Oct 15 2020)
ISSN: 1768-3254 [Electronic] France |
PMID | 32829163
(Publication Type: Journal Article)
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Copyright | Copyright © 2020 Elsevier Masson SAS. All rights reserved. |
Chemical References |
- Carboxylic Acids
- Receptors, Interleukin-8B
- Thiophenes
- beta-Arrestin 2
- Doxorubicin
- Cyclic AMP
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Topics |
- Carboxylic Acids
(chemistry, pharmacology)
- Cell Line, Tumor
- Cell Movement
(drug effects)
- Cyclic AMP
(metabolism)
- Doxorubicin
(pharmacology)
- Drug Design
- Drug Synergism
- Humans
- Inhibitory Concentration 50
- Phosphorylation
(drug effects)
- Receptors, Interleukin-8B
(antagonists & inhibitors, metabolism)
- Signal Transduction
(drug effects)
- Structure-Activity Relationship
- Thiophenes
(chemistry)
- beta-Arrestin 2
(metabolism)
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