Signaling effects of demethylasterriquinone B1, a selective insulin receptor modulator.
A possible breakthrough in the treatment of diabetes was made with the discovery that a fungal natural product, demethylasterriquinone B1 (DAQ B1), is an orally active, small-molecule mimic of insulin. Subsequent work has shown that the glucose-lowering effects of DAQ B1 are not accompanied by enhanced vascular proliferation, which is a side effect of chronic insulin administration that can lead to arteriosclerosis. Our recent short and modular total synthesis of DAQ B1 could be readily modified to create congeners and afforded ample supplies of the natural product, which permitted intracellular signal transduction of DAQ B1 to be examined. The activities of DAQ B1 and over a dozen related structures were studied for insulin receptor (IR) and insulin receptor substrate-1 phosphorylation. Examination of the effect of DAQ B1 on kinases downstream of the IR in insulin signal transduction showed selective activation of Akt kinase (a metabolic effect) but not of extracellular-regulated kinase (a proliferative effect). The influence of DAQ B1 on gene expression (determined by a microarray study) was also divergent from that of insulin, which activates both proliferative and metabolic pathways. The action of DAQ B1 as a selective insulin receptor modulator can be accounted for by its ability to selectively activate one kinase among the many emanating from insulin receptor autophosphorylation and its reduced effects on gene expression.
Department of Medicine 0673 University of California-San Diego, 9500 Gilman Drive La Jolla, California 92093, USA. mwebster@ucsd.edu
Nicholas J G
NJ
Webster
Kaapjoo
K
Park
Michael C
MC
Pirrung
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000528:radiation effects; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D007328:Insulin / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D007211:Indoles; D007328:Insulin; C119066:L 783281; D011809:Quinones; D015682:Retroviridae Proteins, Oncogenic; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051058:Oncogene Protein v-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose