PRECLINICAL AND CLINICAL PHARMACOLOGY OF PROTEIN KINASE ANTAGONISTS

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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-1-methyl)-piperidinyl]-4H- 1-benzopyran-4-one] is a flavone which inhibits cell growth with IC50s 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 G1 or G2, and the occurrence of a G2 block can be related to decreased phosphorylation on tyrosine of the p34cdc2 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 revealed that UCN01 and UCN02 inhibit potently the PKC alpha, Beta and gamma isoform, but not the zeta isoform. The delta and epsilon isoforms are inhibited with intermediate potency. In addition, the compound's ability to inhibit T-cell leukemia growth can be disassociated from inhibition of PKC. Thus, additional targets for UCN01 need to be considered. AG957 is a tyrphostin with potent capacity to inhibit the bcr-abl fusion protein tyrosine kinase activity both in biochemical assays of immunoprecipitated kinase activity and in living cells. The relation of this activity to inhibition of cell growth is under investigation.