Discovery of Novel CXCR2 Inhibitors Using Ligand-Based
Pharmacophore Models
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Abstract
The
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.
CXCR2 and its ligand, CXCL8, are implicated in a number of inflammation-mediated
diseases such as chronic obstructive pulmonary disease, cystic fibrosis,
and cancer. Though the development of CXCR2-specific small-molecule
inhibitors as anti-inflammatory agents has been pursued by pharmaceutical
companies within the past decade, there are currently no clinically
approved CXCR2 inhibitors. A pharmacophore model based on previously
reported CXCR2 antagonists was developed to screen a database of commercially
available compounds. Small-molecule compounds identified from the
pharmacophore screening were selected for in vitro screening in a
cell-based CXCR2-mediated β-arrestin-2 recruitment assay and
further characterized in several cell-based assays and lipopolysaccharide
(LPS)-induced lung inflammation studies in mice. CX compounds identified
from pharmacophore modeling inhibited cell migration, lung and colon
cancer cell proliferation, and colony formation. Mechanistic studies
of CX4152 showed that this compound inhibits CXCR2 signaling through
downregulation of surface CXCR2. Additionally, CX4152 significantly
inhibits CXCL8-mediated neutrophil migration and LPS-induced lung
inflammation in mice. Using a CXCR2-inhibitor-based pharmacophore
model, we identified a novel set of sulfonamides from a diverse library
of small molecules. These compounds inhibit CXCR2/β-arrestin-2
association, cell migration and proliferation, and acute inflammation
in mouse models. CX compounds identified from our pharmacophore models
are potential leads for further optimization and development as anti-inflammatory
and anticancer agents