In vitro activity: Navarixin (formerly known as MK-7123, SCH527123, or PS291822) is a novel potent and specific allosteric antagonist of CXCR1 and CXCR2 with antitumor activity and is able to sensitize cells to oxaliplatin in preclinical colon cancer models. It has Kd values of 41 nM for cynomolgus CXCR1 and 0.20 nM, 0.20 nM, 0.08 nM for mouse, rat and cynomolgus monkey CXCR2, respectivelly. Navarixin binding to CXCR1 and CXCR2 was both saturable and reversible. Although Navarixin bound to CXCR1 with good affinity (K(d) = 3.9 +/- 0.3 nM), the compound is CXCR2-selective (K(d) = 0.049 +/- 0.004 nM). Taken together, the data show that Navarixin represents a novel, potent, and specific CXCR2 antagonist with potential therapeutic utility in a variety of inflammatory conditions.

Kinase Assay: Navarixin (formerly known as MK-7123, SCH527123, or PS291822) is a novel potent and specific allosteric antagonist of CXCR1 and CXCR2 with antitumor activity and is able to sensitize cells to oxaliplatin in preclinical colon cancer models. It has Kd values of 41 nM for cynomolgus CXCR1 and 0.20 nM, 0.20 nM, 0.08 nM for mouse, rat and cynomolgus monkey CXCR2, respectivelly. Navarixin binding to CXCR1 and CXCR2 was both saturable and reversible.

Cell Assay: Recombinant cells are resuspended at 1×106/mL in assay buffer (phenol red free-RPMI 1640 supplemented with 2% FBS). Human neutrophils are resuspended at 2 × 106/mL in the same assay buffer containing 5% FBS. CXCL1 binds only CXCR2 with high affinity, whereas CXCL8 binds both CXCR1 and CXCR2 with high affinity. Chemoattractants (30 μL) diluted in assay buffer are dispensed into the bottom wells of disposable microchemotaxis plates, which are then covered with filter. Cells are preincubated with Navarixin (1-300 nM) in a CO2 incubator for 90 min. Cell aliquots (25 μL) are applied to each spot on the filter. After incubation (90 min for BaF/3 cells and 30 min for PMN in a CO2 incubator), the filters are removed. Migrated cells in the bottom wells are transferred to a Microlite luminometer plate, and 25 μL of ATPlite one-step are added to each well. After incubation at room temperature for 10 min, luminescence intensity is measured using a luminometer.

Rats: 0.1-3 mg/kg, p.o.; formulated in 0.4% methylcellulose; oral