PRECLINICAL PHARMACOLOGY OF PROTEIN KINASE ANTAGONISTS

蛋白激酶活性对蛋白激酶的作用具有明显的重要性。 多种生长因子和细胞癌基因。 因此，我们认为， 蛋白激酶活性中断可能导致新的治疗 剂. 已经研究了三类化合物，所有这些化合物都具有 已证实的抑制丝氨酸/苏氨酸或酪氨酸的能力 激酶。 AG 17和AG 592是厄布他汀的tyrphostin类似物。 这些化合物 都能抑制许多乳腺癌细胞系的生长， IC 50约为0.5-5 μ m。 细胞生长的抑制并不 与已知的酪氨酸激酶活性的表达相关， 这组细胞系。 UCN-01和UCN-02，星形孢菌素的衍生物，抑制了 肺癌和前列腺癌细胞系，IC 50在0.1和1 μ m之间。 发现这些化合物具有广泛但非选择性的细胞毒性 在NCI-Developmental Therapeutics Program屏幕中， 化合物. 其生长抑制作用的机制并不 清楚 L 86 -8275是一种黄酮类化合物，已知其抑制EGF受体 激酶和cAMP依赖性激酶。 它抑制了乳房的生长 IC 50约为0.1 μ m的癌细胞系。 机械论 对这种化合物的研究表明， 在添加后8小时内合成DNA、RNA和蛋白质; 导致细胞周期G2期阻滞;其生长抑制 效果是可逆的。 因此，它的活性和效力使其 与其他先前描述的黄酮类化合物。 后续的研究将集中在是否上述生长抑制 作用与抑制激酶活性有关， 这些案件，以及是否有增加的活动， 常规细胞毒性剂通过这些化合物。

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.