Upon tissue injury and infection both stressed and dying cells can release proteins that
normally reside inside the cells. Some of the released proteins become ligands of various cell surface
receptors expressed by local cells and such proteins are denoted as damage associated molecular
patterns (DAMPs). Binding of some DAMPs to certain cell surface receptors induces signals
emanating in the production of pro-inflammatory cytokines, ultimately leading to an inflammatory
response. Our laboratory is interested in the S100A9 protein, a bona fide DAMP protein. This protein
normally resides inside monocytes and neutrophils and in these cells it forms heterodimers with the
S100A8 protein. The S100A8/A9 heterodimer is released in large amounts during several types of
inflammatory disease and is currently used clinically as a biomarker in some diseases. The fact that several different proinflammatory
functions have been ascribed to this protein makes it a potential target for the development of small
molecule inhibitors. We have developed several such inhibitors, some of which are already in phase III clinical development.
This review describes our efforts to investigate the biological functions of the S100A9 protein as well as our ongoing
efforts of developing second-generation, more specific, small molecule inhibitors of its pro-inflammatory functions.
Keywords: Cancer, DAMP, inflammation, inhibitors, receptor, S100 proteins.
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