SB 225002

SB 225002 is a potent and selective CXCR2 chemokine receptor antagonist with IC50 value of 22nM [1].
CXCR2 is a member of the G-protein-coupled receptor family, which is responsible for neutrophil chemotaxis and margination induced by IL-8 [1].
SB 225002 is a potent and selective non-peptide inhibitor of CXCR2. It prevented IL-8 binding to CXCR2 with IC50 value of 22 nM and showed >150-fold selectivity over CXCR1. In HL60 cells, SB 225002 potently prevented IL-8 and GROa-induced neutrophil chemotaxis [1]. In CDDP-resistant and -sensitive OVCA cell lines, SB225002 induced apoptosis in both wild-type and p53-deficient cells in a p53-independent way and promoted mitotic catastrophe [2].
In rabbits, SB 225002 blocked IL-8-induced neutrophil margination [1]. In experimental colitis mice induced by TNBS, SB225002 reduced neutrophil influx, IL-1 , MIP-2, and keratinocyte-derived chemokine (KC) levels, MPO activity and the expression of vascular endothelial growth factor. While, levels of IL-4 and IL-10 were increased significantly in the colons of mice [3].
References:
[1]. White JR, Lee JM, Young PR, et al. Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration. J Biol Chem, 1998, 273(17): 10095-10098.
[2]. Du M, Qiu Q, Gruslin A, et al. SB225002 promotes mitotic catastrophe in chemo-sensitive and -resistant ovarian cancer cells independent of p53 status in vitro. PLoS One, 2013, 8(1): e54572.
[3]. Manjavachi MN, Quintão NL, Campos MM, et al. The effects of the selective and non-peptide CXCR2 receptor antagonist SB225002 on acute and long-lasting models of nociception in mice. Eur J Pain, 2010, 14(1): 23-31.

Characterization of the molecular interactions of interleukin-8 (CXCL8), growth related oncogen alpha (CXCL1) and a non-peptide antagonist (SB 225002) with the human CXCR2.[Pubmed:12628493]

Biochem Pharmacol. 2003 Mar 1;65(5):813-21.

Neutrophil recruitment to inflammatory sites is mediated by two related receptors: CXC chemokine receptors 1 (CXCR1) and 2 (CXCR2). Both receptors share two ligands, interleukin-8 (CXCL8) and GCP-2 (CXCL6), whereas several chemokines, including growth related oncogen alpha (CXCL1) and a non-peptide antagonist (SB 225002) are specific for CXCR2. The objective of this study was to map the different amino acids involved in the binding and activation/inhibition of human CXCR2. This was performed by exchanging non-conserved amino acids of CXCR2 with their counterparts in CXCR1. The mutants generated showed that: (a) for CXCL8 binding, the N-terminus of CXCR1 and the second extra-cellular loop of CXCR2 are determinant, the N-terminus of CXCR2 is not sufficient and the transmembrane domain seven is probably involved; (b) for CXCL1, the N-terminus of CXCR2 is necessary but not sufficient for binding. The activation study indicated that amino acids critical for activation are not necessarily involved in binding process. Finally, the mechanism of binding of a non-peptide antagonist on CXCR2 was investigated: it occurred through epitopes (a) which were disseminated within the receptor, (b) which differed according to the use of CXCL8 or CXCL1 as a competitor and (c) which did not necessarily overlap with agonist binding sites. We also showed that inhibition of binding and inhibition of activation involved different amino acids.

Interleukin-8 stimulates human immunodeficiency virus type 1 replication and is a potential new target for antiretroviral therapy.[Pubmed:11483765]

J Virol. 2001 Sep;75(17):8195-202.

Production of the C-X-C chemokines interleukin-8 (IL-8) and growth-regulated oncogene alpha (GRO-alpha) in macrophages is stimulated by exposure to human immunodeficiency virus type 1 (HIV-1). We have demonstrated previously that GRO-alpha then stimulates HIV-1 replication in both T lymphocytes and macrophages. Here we demonstrate that IL-8 also stimulates HIV-1 replication in macrophages and T lymphocytes. We further show that increased levels of IL-8 are present in the lymphoid tissue of patients with AIDS. In addition, we demonstrate that compounds which inhibit the actions of IL-8 and GRO-alpha via their receptors, CXCR1 and CXCR2, also inhibit HIV-1 replication in both T lymphocytes and macrophages, indicating potential therapeutic uses for these compounds in HIV-1 infection and AIDS.

Identification of a potent, selective non-peptide CXCR2 antagonist that inhibits interleukin-8-induced neutrophil migration.[Pubmed:9553055]

J Biol Chem. 1998 Apr 24;273(17):10095-8.

Interleukin-8 (IL-8) and closely related Glu-Leu-Arg (ELR) containing CXC chemokines, including growth-related oncogene (GRO)alpha, GRObeta, GROgamma, and epithelial cell-derived neutrophil-activating peptide-78 (ENA-78), are potent neutrophil chemotactic and activating peptides, which are proposed to be major mediators of inflammation. IL-8 activates neutrophils by binding to two distinct seven-transmembrane (7-TMR) G-protein coupled receptors CXCR1 (IL-8RA) and CXCR2 (IL-8RB), while GROalpha, GRObeta, GROgamma, and ENA-78 bind to and activate only CXCR2. A chemical lead, which selectively inhibited CXCR2 was discovered by high throughput screening and chemically optimized. SB 225002 (N-(2-hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea) is the first reported potent and selective non-peptide inhibitor of a chemokine receptor. It is an antagonist of 125I-IL-8 binding to CXCR2 with an IC50 = 22 nM. SB 225002 showed >150-fold selectivity over CXCR1 and four other 7-TMRs tested. In vitro, SB 225002 potently inhibited human and rabbit neutrophil chemotaxis induced by both IL-8 and GROalpha. In vivo, SB 225002 selectively blocked IL-8-induced neutrophil margination in rabbits. The present findings suggest that CXCR2 is responsible for neutrophil chemotaxis and margination induced by IL-8. This selective antagonist will be a useful tool compound to define the role of CXCR2 in inflammatory diseases where neutrophils play a major role.