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Broad Spectrum Chemokine Inhibitors (BSCIs)


BSCIs are an entirely novel class of anti-inflammatory agents that inhibit the migration of several types of leukocytes (primarily granulocytes and monocytes) in response to a wide range of chemokines (including MCP-1, SDF-1α, RANTES, MIP-1α and IL-8) while having no effect on migration induced by other chemoattractants (such as fMLP or C5a). As a result, the primary functional pharmacology of BSCIs in vitro is the inhibition of chemokine-induced migration at sub-nanomolar concentrations.

However, the activity of BSCIs has been shown to be mediated not through binding to chemokine receptors but through the selective interaction with a single well-characterized receptor (“BSCI receptor”), revealing an unexpected mechanism of action for this new class of anti-inflammatory agents. BSCIs act on this “BSCI receptor” to generate intracellular signals, including activation of MAP kinases and PKC isoforms, which effectively blind the target cell to the directional signals ordinarily discerned from chemokine gradients.  Since the “BSCI receptor” is abundant on monocytes, macrophages and granulocytes (including neutrophils, eosinophils, basophils and mast cells), but is present at much lower levels on both B and most T lymphocytes, the result is an anti-inflammatory agent which powerfully inhibits pathogenic inflammatory signals, while leaving the adaptive immune system intact.  To our knowledge, the BSCIs are the only class of anti-inflammatory agents yet described with this mode of action.

 

FXT has developed several families of compounds with potent and powerful BSCI activity. Representative BSCIs showed efficacy in a range of animal inflammatory disease models [see examples of published studies in the Publications section]

FX125L is the lead BSCI, with completed Phase I clinical trials in the USA. The clinical indications targeted with FX125L include respiratory disorders such as asthma and COPD, supported by numerous studies in animal models that consistently suggested that in the clinic FX125L may have similar efficacy but better safety than corticosteroids and superior efficacy than montelukast. Other BSCIs have also been identified as back up molecules to FX125L and as candidates for development as topical anti-inflammatory agents.