The chemokine receptor CXCR4 and its ligand CXCL12 are involved in the progression and dissemination of a diverse number of solid and hematological malignancies. Binding CXCL12 to CXCR4 activates a variety of intracellular signal transduction pathways that regulate cell chemotaxis, adhesion, survival, proliferation, and apoptosis[1]. LIT-927 is a locally and orally active CXCL12 neutraligand with anti-inflammatory effect, with a Ki of 267 nM for CXCL12 binding to its specific receptor CXCR4[2]. LIT-927 is selected as lead neutraligand and characterized its activity (IC50) in vivo in a dose–response efficacy study on eosinophil recruitment in mouse model. LIT-927 at 10 μM is able to inhibit the increase in intracellular calcium concentration in EGFP-CXCR4+ HEK cells in response to CXCL12, while it has no effect on calcium responses triggered by either CCL17 or CCL22 on EGFP-CXCR4+ HEK cells, CCL5 on EGFP-CCR5+ HEK cells, or CCL2 on EGFP-CCR2+ HEK cells. These results demonstrate the high selectivity of LIT-927 toward CXCL12 vs other chemokines also involved in asthma[2]. More interestingly, LIT-927 displayed very good to excellent in vivo activity, inhibiting eosinophil infiltration by 48%[2]. LIT-927 reduced eosinophil recruitment in a murine model of allergic airway hypereosinophilia, LIT-927 was the only one to display inhibitory activity following oral administration[2].
作用机制
Docking of LIT-927 to this pocket at the vicinity of Trp57 is possible at the condition to allow side-chain flexibility for three residues (Arg20, Trp57, and Tyr61) that would control the entry to the Trp57 pocket.
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