Design of a selective insulin receptor tyrosine kinase inhibitor and its effect on glucose uptake and metabolism in intact cells
- Merck Sharp and Dohme Research Labs., Rahway, NJ (USA)
An inhibitor of the insulin receptor tyrosine kinase (IRTK), (hydroxy-2-napthalenylmethyl)phosphonic acid, was designed and synthesized and was shown to be an inhibitor of the biological effects of insulin in vitro. With a wheat germ purified human placental insulin receptor preparation, this compound inhibited the insulin-stimulated autophosphorylation of the 95-kDa {beta}-subunit of the insulin receptor. The ability of the kinase to phosphorylate an exogenous peptide substrate, angiotensin II, was also inhibited. Half-maximal inhibition of basal and insulin-stimulated human placental IRTK activity was found at concentrations of 150 and 100 {mu}M, respectively, with 2 mM angiotensin II as the peptide substrate. The inhibitor was found to be specific for tyrosine kinases over serine kinases and noncompetitive with ATP. The inhibitor was converted into various (acyloxy)methyl prodrugs in order to achieve permeability through cell membranes. These prodrugs inhibited insulin-stimulated autophosphorylation of the insulin receptor 95-kDa {beta}-subunit in intact CHO cells transfected with human insulin receptor. Inhibition of insulin-stimulated glucose oxidation in isolated rat adipocytes and 2-deoxyglucose uptake into CHO cells was observed with these prodrugs. The data provide additional evidence for the involvement of the insulin receptor tyrosine kinase in the regulation of glucose uptake and metabolism. These results and additional data reported herein suggest that this class of prodrugs and inhibitors will be useful for modulating the activity of a variety of tyrosine kinases.
- OSTI ID:
- 5050043
- Journal Information:
- Biochemistry; (USA), Vol. 28:13; ISSN 0006-2960
- Country of Publication:
- United States
- Language:
- English
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CARBON 14 COMPOUNDS
UPTAKE
ENZYME INHIBITORS
BIOSYNTHESIS
GLUCOSE
INSULIN
RADIORECEPTOR ASSAY
CHO CELLS
ENZYME ACTIVITY
FAT CELLS
IODINE 125
MAN
PHOSPHOTRANSFERASES
RATS
RECEPTORS
TYROSINE
ALDEHYDES
AMINO ACIDS
ANIMAL CELLS
ANIMALS
BETA DECAY RADIOISOTOPES
CARBOHYDRATES
CARBOXYLIC ACIDS
CONNECTIVE TISSUE CELLS
DAYS LIVING RADIOISOTOPES
ELECTRON CAPTURE RADIOISOTOPES
ENZYMES
HEXOSES
HORMONES
HYDROXY ACIDS
INTERMEDIATE MASS NUCLEI
IODINE ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
LABELLED COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
MONOSACCHARIDES
NUCLEI
ODD-EVEN NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
PEPTIDE HORMONES
PHOSPHORUS-GROUP TRANSFERASES
PRIMATES
PROTEINS
RADIOISOTOPES
RODENTS
SACCHARIDES
SOMATIC CELLS
SYNTHESIS
TRACER TECHNIQUES
TRANSFERASES
VERTEBRATES
550601* - Medicine- Unsealed Radionuclides in Diagnostics