[HTML][HTML] Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides

P Björk, A Björk, T Vogl, M Stenström, D Liberg… - PLoS …, 2009 - journals.plos.org
P Björk, A Björk, T Vogl, M Stenström, D Liberg, A Olsson, J Roth, F Ivars, T Leanderson
PLoS biology, 2009journals.plos.org
Despite more than 25 years of research, the molecular targets of quinoline-3-carboxamides
have been elusive although these compounds are currently in Phase II and III development
for treatment of autoimmune/inflammatory diseases in humans. Using photoaffinity cross-
linking of a radioactively labelled quinoline-3-carboxamide compound, we could determine
a direct association between human S100A9 and quinoline-3-carboxamides. This
interaction was strictly dependent on both Zn++ and Ca++. We also show that S100A9 in the …
Despite more than 25 years of research, the molecular targets of quinoline-3-carboxamides have been elusive although these compounds are currently in Phase II and III development for treatment of autoimmune/inflammatory diseases in humans. Using photoaffinity cross-linking of a radioactively labelled quinoline-3-carboxamide compound, we could determine a direct association between human S100A9 and quinoline-3-carboxamides. This interaction was strictly dependent on both Zn++ and Ca++. We also show that S100A9 in the presence of Zn++ and Ca++ is an efficient ligand of receptor for advanced glycation end products (RAGE) and also an endogenous Toll ligand in that it shows a highly specific interaction with TLR4/MD2. Both these interactions are inhibited by quinoline-3-carboxamides. A clear structure-activity relationship (SAR) emerged with regard to the binding of quinoline-3-carboxamides to S100A9, as well as these compounds potency to inhibit interactions with RAGE or TLR4/MD2. The same SAR was observed when the compound's ability to inhibit acute experimental autoimmune encephalomyelitis in mice in vivo was analysed. Quinoline-3-carboxamides would also inhibit TNFα release in a S100A9-dependent model in vivo, as would antibodies raised against the quinoline-3-carboxamide–binding domain of S100A9. Thus, S100A9 appears to be a focal molecule in the control of autoimmune disease via its interactions with proinflammatory mediators. The specific binding of quinoline-3-carboxamides to S100A9 explains the immunomodulatory activity of this class of compounds and defines S100A9 as a novel target for treatment of human autoimmune diseases.
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