Protein kinases represent a final common pathway for the activities of a variety of oncogenes and growth factors. Agents which interrupt the action of protein kinases would therefore be of potential value in neoplasms which depend on particular protein kinases for their pathogenesis or maintenance. Three classes of compound are being studied in an effort to develop this class of agents. L86-8275; (-)cis- 5,7dihydroxy- 2-(2-chlorophenyl)-8[4-(3-hydroxy-l-methyl)-piperidinyl]-4H-l- benzopyran-4-one] is a flavone which inhibits cell growth with IC(50)s of 20-200 nM. It was initially selected for study because of antitumor activity in a variety of lung and breast tumor models in vivo, and as an inhibitor of EGF receptor kinase. Recent experiments have shown that the drug can arrest cells either in G, or G2 and the occurrence of a G2 block can be related to decreased phosphorylation on tyrosine of the p34(cdc2) kinase. Further experiments will determine whether this is the basis for cell cycle arrest. UCN-01 and UCN-02 are diastereomers, derivatives of staurosporine. These drugs were initially screened as inhibitors of protein kinase C, but with evidence of antitumor effect in the A431 squamous carcinoma model. Recent experiments have observed potent inhibition of breast carcinoma cell growth, with a pattern of sensitivity to and reversibility of effect of the two diastereomers which correlates with protein kinase C isoform expression. Specifically, relative reversibility of inhibition of cell growth is observed in cell lines with prominent expression of protein kinase C alpha; irreversible growth inhibition is observed in cells with low or absent protein kinase C alpha and prominent expression of protein kinase C zeta. In addition , a block to cell cycle progression in G1 is evident, with a block in S phase at higher concentrations. AG17 and AG592 represent tyrphostin analogs of erbstatin which screening studies revealed to be the most potent of a series of tyrphostins in inhibition of breast carcinoma cells. Shortly after addition of AG17, DNA synthesis is inhibited. The relation to inhibition of tyrosine phosphorylation is under investigation.
