title: Pyrimidine-based compounds modulate CXCR2-mediated signaling and receptor turnover.
abstract: Chemokine receptor CXCR2 is expressed on various immune cells and is essential for neutrophil recruitment and angiogenesis at sites of acute and chronic inflammation caused by tissue injury or infection. Because of its role in inflammation, it has been implicated in a number of immune-mediated inflammatory diseases such as psoriasis, arthritis, COPD, cystic fibrosis, asthma, and various types of cancer. CXCR2 and its ligands are up-regulated in cancer cells as well as the tumor microenvironment, promoting tumor growth, angiogenesis, and invasiveness. Although pharmaceutical companies have pursued the development of CXCR2-specific small-molecule inhibitors as anti-inflammatory agents within the last decades, there are currently no clinically approved CXCR2 inhibitors. Using a high-throughput, cell-based assay specific for CXCR2, we screened an in-house library of structurally diverse compounds and identified a class of pyrimidine-based compounds that alter CXCR2-mediated second messenger signaling. Our lead compound, CX797, inhibited IL8-mediated cAMP signaling and receptor degradation while specifically up-regulating IL8-mediated β-arrestin-2 recruitment. CX797 also inhibited IL8-mediated cell migration. Mechanistic comparison of CX797 and a previously reported CXCR2 inhibitor, SB265610, show these two classes of compounds have a distinct mechanism of action on CXCR2.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California , 1985 Zonal Avenue, Los Angeles, California 90033, United States.
authors.forename: Helen
authors.initials: H
authors.lastname: Ha
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D016209:Interleukin-8 / Q000378:metabolism; D019169:Jurkat Cells; D011743:Pyrimidines / Q000494:pharmacology*; D023063:Receptors, Interleukin-8B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D059016:Tumor Microenvironment / Q000187:drug effects; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D000893:Anti-Inflammatory Agents; D019390:Arrestins; C508606:CXCL8 protein, human; D016209:Interleukin-8; D011743:Pyrimidines; D023063:Receptors, Interleukin-8B; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000242:Cyclic AMP; C030986:pyrimidine