Discovery of a small molecule insulin receptor activator

Insulin elicits diverse: biological responses in many tissues and cell type s by binding to its specific receptor. The insulin receptor (IR) is a tetra mer consisting of two extracellular a subunits and two membrane-spanning 13 subunits. The binding of insulin to the receptor causes conformational cha nges that lead to autophosphorylation and activation of the tyrosine kinase intrinsic to the beta subunits. Insulin receptor transphosphorylates sever al immediate substrates, resulting in modulation of a cascade of downstream signal transduction molecules. In order to discover small molecules that a ctivate the human insulin receptor tyrosine kinase (IRTK), a cell-based ass ay was established and utilized to screen a collection of synthetic chemica ls and natural product extracts. This effort led to the identification of a nonpeptidyl, small molecule, insulin-mimetic compound (demethylasterriquin one B-1, DMAQ-B1) that was isolated from a mixture of metabolites produced by a tropical endophytic fungus, Pseudomassaria sp. This compound induced h uman IRTK activation and increased tyrosine phosphorylation of IR 13 subuni t. It mediated insulin-like effects, including insulin receptor substrate-1 (IRS-I) phosphorylation and activation of phosphotidylinositide 3-kinase a nd Akt kinase. DMAQ-B1 also exhibited an insulin-like effect on glucose upt ake in adipocytes and skeletal muscle tissue. Furthermore, the compound was relatively selective for IR vs. insulin-like growth factor-I (IGF-I) recep tor and other homologous receptor tyrosine kinases. In addition, it activat ed partially purified native IR or recombinant IR kinase, demonstrating the direct interaction of the small molecule with the IR. Oral administration of DMAQ-B1 resulted in significant glucose lowering in two mouse models of diabetes. Thus, DMAQ-B1 represents the first orally active insulin-mimetic agent. Pharmaceutical intervention aimed at augmenting IR function ultimate ly may prove beneficial as a novel therapeutic option in patients with diab etes.