PRECLINICAL AND CLINICAL PHARMACOLOGY OF PROTEIN KINASE ANTAGONISTS

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Agents which disrupt protein kinase action would be of interest to develop because protein kinases represent a final common pathway for the actions of diverse oncogenes and growth factors. The challenge is to define compounds which are selective and yet retain therapeutic index in vivo. Three classes of compounds are being studied in LBC to define the basis for therapeutic index and potential efficacy. Flavopiridol(NSC 649890; Behringwerke L86-8275) is a flavone which prior studies had shown inhibits growth of various tumor cell lines with IC50s of between 20 and 200 nM, and can block cell cycle progression either in G2 or in G1, as well as retard progression through S phase. We have demonstrated that this compound is a potent direct inhibitor of p34cdc2 kinase isolated from either breast carcinoma cells or sea star. The Ki for ATP (competitive inhibition) is 46 nM, and the Ki for peptide substrate (noncompetitive inhibition) is 140 nM. In addition, flavopiridol decreases both Thr and Tyr phosphorylations of p34cdc2. The second compound under study is UCN- 01(NSC 638850). This compound was originally isolated as a selective protein kinase C antagonist. We have confirmed selectivity for PKC isoforms, with IC50s of 29, 34 and 30nM for PKCs alpha, beta, and gamma, respectively. PKCs delta and epsilon are less potently affected(IC50s of 530 and 590nM respectively), and PKC zeta is unaffected. The relationship of cell growth inhibition to PKC inhibition is currently under evaluation. In the final category of compound under evaluation, we have defined that the tyrphostin AG957 is a lead structure for compounds which inhibit p210bcr-abl tyrosine kinase in living cells. This effect is followed shortly by decrease in DNA synthesis, with no immediate effect on cell viability. The molecular basis for this result is under study.