Three approaches toward the inhibition of tyrosine-specific kinases are being investigated. In the first approach, opiates were found to inhibit dermal growth factor receptor (EGFR) autophosphorylation at low concentrations. This was reversed at higher concentrations. (+)-Morphine 1, the analgesically inactive isomer of morphine, did not show this reversal of inhibition at higher concentrations. A series of phosphonate-containing structures 2 was prepared. None of these were active against p56lck kinase, and testing is presently continuing in the EGFR system. Finally, the known EGFR kinase inhibitor 6 was prepared and shown to inhibit p56lck autophosphorylation without inhibiting exogenous substrate phosphorylation. Erbstatin 7, a potent inhibitor of EGFR kinase, was shown to be inactive against p56lck. Analogs 8 and 9, which combine features of both 6 and erbstatin were inactive. Analogs are presently being prepared to study selective inhibition of p56lck autophosphorylation.
