Discovery of a Small Molecule Insulin Receptor Activator

Abstract

Insulin elicits diverse biological responses in many tissues and cell types by binding to its specific receptor. The insulin receptor (IR) is a tetramer consisting of two extracellular a subunits and two membrane-spanning p subunits. The binding of insulin to the receptor causes conformational changes that lead to autophosphorylation and activation of the tyrosine kinase intrinsic to the S subunits.

MLR-1023 Is a Potent and Selective Allosteric Activator of Lyn Kinase In Vitro That Improves Glucose Tolerance In Vivo

“…There are also examples of small molecules directly activating a kinase through a conformational change independent of changing the phosphorylation state of the enzyme. For example, the insulin receptor tyrosine kinase activator 2-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]-3,6-dihydroxy-5-[7-(3-methyl-2-butenyl)-1H-indol-3-yl]-2,5-cyclohexadiene-1,4-dione L-783,281 and its structural analogs activate the enzyme by inducing a conformational change that removes autoinhibition and allows ATP access to its binding site, which in turn drives kinase activity (Zhang et al, 1999;Salituro et al, 2001).…”

A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses

“…Indeed, the past years have witnessed the start of a trend in synthesizing nonpeptidic small molecule-mimics that can inhibit protein-protein interaction or mimic one of the interacting proteins (24). Thus, low molecular weight agonists for EPO receptor (25) and insulin receptor tyrosine kinase (26), as well as inhibitors of chemokinechemokine receptor interaction (27) and Myc͞Max dimerization (28), were described. The present work adds another example to the list of small molecules that can specifically interfere with protein-protein interaction.…”

Natural Products from Plant-Associated Microorganisms: Distribution, Structural Diversity, Bioactivity, and Implications of Their Occurrence

“…Two additional asterriquinones (100d and 100e) and three of their derivatives (103 -105) thought to be "artifacts" have also been characterized from this endophyte. 59 However, it is possible that 103 -105 are genuine metabolites arising from DMAQ-B1 (100c) as a result of enzymatic hydroxylation, epoxidation, and hydroperoxy-mediated p-benzoquinone ring contraction 87a ( Figure S1, Supporting Information). Two new antibiotic alkaloids, pyrrocidines A (106a) and B (106b), based on rare 13-membered macrocyclic rings, previously reported from an unidentified fungal strain, have been found to occur in the maize endophyte, Acremonium zeae.…”