Cytokine receptor inhibitors

Princen K, Schols D. HIV chemokine receptor inhibitors as novel anti-HIV drugs. Cytokine Growth Factor Rev 2005 16(6) 659-677. 

Cytokine signaling is strictly regulated at several sites to avoid damages resulting from uncontrolled signal transduction initiated from activated cytokine receptors. A number of cytokine signaling inhibitors have been described. 

Mechanistically, inhibition must not necessarily block the active site itself, but it can exert allosteric effects on the substrate-binding pocket, which thereby enhances or suppresses enzymatic activity. Additional considerations regarding enzymatic reactions are discussed in Reference 86. SAR by NMR has been successfully applied to various systems [i.e., for disrupting intracellular protein-protein binding (87) as well as cytokine-receptor interaction (88)]. High-affinity enzyme inhibitors have been developed by this technique [e.g., for the metalloproteinase Stromelysin (89) and the protein tyrosine phosphatase IB (90)]. 

Rini B, Rixe O, Bukowski R, et al. (2005) AG-013736, a multitarget tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC). ASCO Proc (abstract 4509). 

Specific and nonspecific inhibitors have now been described for many cytokines. Specific inhibitors such as the IL-lra (H4) or soluble receptor components shed from cells may be inhibitory in bioassays (F7). IL-1 and IL-6 in plasma may be bound to carrier proteins such as aj-macroglobulin (B57, Mil). In addition circulating autoantibodies to cytokines have been found in normal individuals. 

Adams, T.E., J.A. Hansen, R. Starr, N.A. Nicola, D.J. Hilton, and N. Billestrup (1998). Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling. J. Biol. Chem. 273, 1285-1287. 

J. R. Heal, S. Bino, G. W. Roberts, J. G. Raynes and A. D. Miller, Mechanistic investigation into complementary (antisense) peptide mini-receptor inhibitors of cytokine interleukin-1, ChemBioChem, 2002, 3, 76-85. 

---