Therapeutic challenges of kinase and phosphatase inhibition and use in anti-diabetic strategy.
The development of kinase and phosphatase inhibitors as novel therapeutic agents has been stimulated by the discovery that most biological processes are controlled by the reversible phosphorylation of proteins. Most of the early results in this area were generated in oncology, at the same time as the human genome, with its 500+ kinases and 100+ phosphatases was deciphered. Because of this, we know a great deal about which processes signalling inhibitors interfere with, but little about the overall consequences. In this study, kinases will be briefly reviewed, followed by some of the early problems in developing kinase inhibitors, as biochemical reagents, and clinically active pharmaceuticals in oncology. The discussion will then switch to the potential role of kinases and phosphatases in controlling the disease process in Type II diabetes. Phosphatase inhibitors should augment insulin receptor tyrosine kinase signalling. Glycogen synthesis and glycogenolysis are phosphorylation dependent, and amenable to kinase inhibition, as are some nuclear hormone receptors, and these will be briefly discussed.
Bridges
A J
AJ
Quatrx Pharmaceutical Co, 777 E. Eisenhower Parkway, Suite 100, Ann Arbor, MI 48108, USA. abridges@quatrx.com
D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism
D004791:Enzyme Inhibitors; D007328:Insulin; D010770:Phosphotransferases; D011972:Receptor, Insulin; D010744:Phosphoric Monoester Hydrolases