Bi-functional Molecules To Degrade Circulating Proteins

The present invention is directed to bi-functional compounds which find use as pharmaceutical agents in the treatment of disease states and/or conditions which are mediated through macrophage migration inhibitory factor (MIF) or immunoglubin G (IgG). The present invention is also directed to pharmaceutical compositions which comprise these bi-functional compounds as well as methods for treating disease states and/or conditions which are mediated through MIF/IgG or where MIF/IgG is a contributing factor to the development and perpetuation of diseases and/or conditions, especially including autoimmune diseases and cancer, among others. The purpose of the present invention is to provide a molecular strategy to lower plasma MIF/IgG level in patients with autoimmune diseases or certain types of cancers. The bi-functional molecule construct is comprised of a MIF/IgG-targeting motif, that is derived from small molecule MIF/IgG ligands, and an ASGPr-targeting motif that binds to hepatocyte asialoglycoprotein receptor (ASGPr). The compounds selectively bind MIF or IgG in plasma and subsequently engage the endo-lysosomal pathway of hepatocytes through ASGPr. As a consequence, MIF/IgG is internalized and degraded by hepatocytes, thus resulting in potential attenuation of corresponding disease symptoms which are modulated through MIF/IgG.