Ha Helen, Neamati Nouri
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California , 1985 Zonal Avenue, Los Angeles, California 90033, United States.
Mol Pharm. 2014 Jul 7;11(7):2431-41. doi: 10.1021/mp500180e. Epub 2014 Jun 4.
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.
趋化因子受体CXCR2在多种免疫细胞上表达，对于在由组织损伤或感染引起的急慢性炎症部位募集中性粒细胞和血管生成至关重要。由于其在炎症中的作用，它与许多免疫介导的炎症性疾病有关，如银屑病、关节炎、慢性阻塞性肺疾病、囊性纤维化、哮喘和各种类型的癌症。CXCR2及其配体在癌细胞以及肿瘤微环境中上调，促进肿瘤生长、血管生成和侵袭。尽管在过去几十年中，制药公司一直在研发CXCR2特异性小分子抑制剂作为抗炎药，但目前尚无临床批准的CXCR2抑制剂。我们使用针对CXCR2的基于细胞的高通量检测方法，筛选了一个内部结构多样的化合物库，并鉴定出一类改变CXCR2介导的第二信使信号的嘧啶类化合物。我们的先导化合物CX797抑制IL8介导的cAMP信号传导和受体降解，同时特异性上调IL8介导的β-抑制蛋白2募集。CX797还抑制IL8介导的细胞迁移。CX797与先前报道过的CXCR2抑制剂SB265610的作用机制比较表明，这两类化合物对CXCR2具有不同的作用机制。
