PRECLINICAL PHARMACOLOGY OF PROTEIN KINASE ANTAGONISTS

蛋白激酶活性对a的作用具有明显的重要性

Protein kinase activity is of clear importance to the action of a variety of growth factors and cellular oncogenes. Therefore, interruption of protein kinase activity could lead to novel therapeutic agents. Three classes of compounds have been studied, all of which have the proven capacity to inhibit either serine/threonine or tyrosine kinases. AG17 and AG592 are tyrphostin analogs of erbstatin. These compounds both inhibit the growth of a number of breast carcinoma cell lines with IC50s of approximately 0.5-5 Um. The inhibition of cell growth does not correlate with the expression of known tyrosine kinase activities in this panel of cell lines. UCN-01 and UCN-02, derivatives of staurosporin, inhibit the growth of lung and prostate carcinoma cell lines, with IC50s between 0.1 and 1 Um. These compounds were found to have broad but non-selective cytotoxicity in the NCI-Developmental Therapeutics Program Screen for active compounds. The mechanism of their growth-inhibitory effect is not clear. L86-8275 is a flavone with known capacity to inhibit both EGF-receptor kinase and CAMP-dependent kinase. It inhibited growth of breast carcinoma cell lines with IC50s of approximately 0.1 Um. Mechanistic studies with this compound reveal that it inhibits macromolecular synthesis of DNA, RNA, and protein within eight hours of addition; it causes a block in the G2 phase of the cell cycle; its growth-inhibitory effect is reversible. Thus, its activity and potency distinguishes it from other previously described flavones. Subsequent studies will focus on whether the above growth-inhibitory effects are relatable to the inhibition of kinase activity in each of these cases, and whether there is augmentation of activity of conventional cytotoxic agents by these compounds.