Pharmacological Characterization of Sch527123, a Potent Allosteric CXCR1/CXCR2 Antagonist

Abstract

In neutrophils, growth-related protein-␣ (CXCL1) and interleukin-8 (CXCL8), are potent chemoattractants (Cytokine 14:27-36, 2001; Biochemistry 42: 2874 -2886, 2003) and can stimulate myeloperoxidase release via activation of the G protein-coupled receptors CXCR1 and CXCR2. The role of CXCR1 and CXCR2 in the pathogenesis of inflammatory responses has encouraged the development of small molecule antagonists for these receptors. The data presented herein describe the phar-, a novel antagonist of both CXCR1 and CXCR2. Sch527123 inhibited chemokine binding to (and activation of) these receptors in an insurmountable manner and, as such, is categorized as an allosteric antagonist. Sch527123 inhibited neutrophil chemotaxis and myeloperoxidase release in response to CXCL1 and CXCL8 but had no effect on the response of these cells to C5a or formyl-methionyl-leucyl-phenylalanine. The pharmacological specificity of Sch527123 was confirmed by testing in a diversity profile against a panel of enzymes, channels, and receptors. To measure compound affinity, we characterized [ 3 H]Sch527123 in both equilibrium and nonequilibrium binding analyses. Sch527123 binding to CXCR1 and CXCR2 was both saturable and reversible. Although Sch527123 bound to CXCR1 with good affinity (K d ϭ 3.9 Ϯ 0.3 nM), the compound is CXCR2-selective (K d ϭ 0.049 Ϯ 0.004 nM). Taken together, our data show that Sch527123 represents a novel, potent, and specific CXCR2 antagonist with potential therapeutic utility in a variety of inflammatory conditions.

Nonpeptidergic Allosteric Antagonists Differentially Bind to the CXCR2 Chemokine Receptor

“…2). The obtained pK i values of both the diarylurea and pyrimidine compounds are in good agreement with earlier published data (White et al, 1998;Podolin et al, 2002;Catusse et al, 2003;Ho et al, 2006;Gonsiorek et al, 2007). All tested compounds were able to inhibit CXCL8-induced ␤-arrestin2 recruitment in human CXCR2-transfected cells, with a rank order of SB332235 ϳ SB265610 Ͼ SB225002 ϳ VUF10948 Ͼ compound 1 Ͼ compound 3 Ͼ compound 2 (Fig.…”

“…Hence, all the CXCR2 antagonists of the different chemical classes tested in this study displace and antagonize CXCL8, most probably via a noncompetitive, allosteric mechanism. This mechanism of action is common for other small antagonists targeting chemokine receptors (Gonsiorek et al, 2007;Verzijl et al, 2008). The allosteric inhibition by the tested CXCR2 antagonists is expected, as in general chemokines, like CXCL8, are thought to bind to the extracellular part of the GPCR protein (Rajagopalan and Rajarathnam, 2006;Allen et al, 2007;Viola and Luster, 2008), notably the N terminus and the extracellular loops.…”

The role of chemokines in B cell chronic lymphocytic leukaemia: pathophysiological aspects and clinical impact

“…In fact, recombinant CXCL8 was shown to protect B-CLL cells from cytotoxic effects caused by the cytostatic drugs chlorambucil and fludarabin [39]. Several approaches to inhibit CXCR1 and CXCR2 have been undertaken, mostly in the context of inflammation in airway diseases, with proven efficacy in several animal models and ongoing phase II clinical trials for chronic obstructive pulmonary disease [41][42][43][44][45]. To date, there is no report on CXCR1/CXCR2 inhibition in B-CLL.…”

The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

“…SCH-527123, as a novel and selective antagonist of the CXCR2, has shown efficacy in the treatment of inflammatory diseases (17). Moreover, Singh and colleagues showed that SCH-527123 treatment inhibited human melanoma cancer growth and colorectal cancer liver metastases by decreasing tumor cell proliferation, angiogenesis, and enhancing the apoptosis of malignant cells (18,19).…”