SB-332235 is an Orally Active CXCR2 Antagonist
Posted On 2021-04-27
Chemokines are low m.w. proteins that modulate the immune response through the chemoattraction and activation of leukocytes. These mediators have four classes. Chemokines in which the first two cysteines are separated by a single, nonconserved amino acid are CXC or chemokines, while those containing adjacent N-terminalcysteine residues are CC or chemokines. CXCR2 signaling is important in regulating oligodendrocyte progenitor cells (OPCs) biology with regard to positional migration and myelination during development. IL8 is a known potent proinflammatory cytokine that exerts its effects through binding to its G protein-coupled receptors CXCR1 and CXCR2. CXCR2 is an adverse prognostic factor in myelodysplastic syndromes (MDS)/AML. It is a potential therapeutic target against immature leukemic stem cell-enriched cell fractions in MDS and AML. In this study, SB-332235 is a potent nonpeptide antagonist of human CXCR2 potently inhibits human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2.
SB-332235 is a potent, orally active nonpeptide CXCR2 antagonist, with an IC50 of 7.7 nM. It displays 285-fold selectivity for CXCR2 over CXCR1. SB-332235 also inhibits acute and chronic models of arthritis in the rabbit. SB-332235 inhibits the viability of acute myeloid leukemia (AML) cells. It also exhibits significantly reduced numbers of total leukocytes in synovial fluids from IL-8-injected knees. SB-332235 inhibits chronic Ag-induced arthritis. Furthermore, IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells.
In summary, SB-332235 is a potent, orally active nonpeptide CXCR2 antagonist. In addition, SB-332235 inhibits acute and chronic models of arthritis in the rabbit. SB-332235 inhibits the viability of AML cells.
Podolin PL, et al. J Immunol. 2002;169(11):6435-6444.