Discovery, structure-activity relationship study and biological evaluation of 2-thioureidothiophene-3-carboxylates as a novel class of C-X-C chemokine receptor 2 (CXCR2) antagonists

• DOI: 10.1016/j.ejmech.2020.112387
• Publication Date: 2020-06-04T06:04:12Z
• Authors: Ding Xue; Wenmin Chen; Nouri Neamati
• Keywords: 0301 basic medicine; Carboxylic Acids; Drug Synergism; Thiophenes; beta-Arrestin 2; Receptors, Interleukin-8B; 3. Good health; Inhibitory Concentration 50; Structure-Activity Relationship; 03 medical and health sciences; Cell Movement; Doxorubicin; Cell Line, Tumor; Drug Design; Cyclic AMP; Humans; Phosphorylation; Signal Transduction

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.