Insulin receptor kinase inhibitor

Fig. 7.2-12 Bisubstrate analog inhibitors of the insulin receptor kinase with varying linkers.

IGF-l-RTK, insulin-like growth factor-1 receptor tyrosine kinase IGF-2, insulin-like growth factor-2 IGF-2-RTK, insulin-like growth factor-2 receptor tyrosine kinase iGlu-R, inhibitory glutamate receptor IKK, inhibitor kB kinase IL, interleukin IL-1P, interleukin-1P IL-ip-R, interleukin-ip receptor IL-1, interleukin-1 IL-8, interleukin-8 IL-8-R, interleukin-8-receptor lie, isoleucine Im, imidazole... 

The tyrosine kinase class of receptors includes receptors for insulin and insulin-like growth factors, and epidermal growth factor. The kinase activity appears to be essential for the activity of these receptors (Cadena and Gill, 1992 Baulieu, 1990). Novel receptor-specific inhibitors of the tyrosine kinase activity are... 

Vanadate (VOj or H2VO4 ) was first recognized in 1979 as having insulin mimetic properties [258]. Since then, vanadate and vanadyl (V ) have been shown to mimic most but not all biological actions of insulin in vitro and to lower blood glucose in streptozotocin-treated rats [259, 260]. Vanadate is a potent inhibitor of phosphotyrosine phosphatases, an interesting activity since the insulin receptor is a tyrosine kinase, and some of the actions of insulin have been proposed to take place via autophosphorylation of the insulin receptor and phosphorylation of cellular substrates on tyrosine residues [261]. Some recent developments on the mechanism and the in vivo activity of vanadate and its derivatives are presented here. 

A recent case described the synthesis of more stable bioisosteres of inhibitors of the insulin-like growth factor-1 receptor kinase (Figure 15.43). Based on the structure of AG 538 ° which contains two catechol rings and is sensitive to oxidation in cell, a new series of kinase inhibitors were developed. The catechol moiety was replaced by a benzoxazolone ring resistant to oxidation yielding two compounds GB19 and AGL2263 which maintain same potency as AG 538. 

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