PRECLINICAL AND CLINICAL PHARMACOLOGY OF PROTEIN KINASE ANTAGONISTS

蛋白激酶是一条最终的共同途径，它的活性 多种癌基因和生长因子。中断的代理 因此，蛋白激酶的作用在 依赖于特定蛋白激酶的肿瘤 发病或维持。目前正在研究三类化合物 努力培养这类特工。L86-8275；(-)顺- 5，7dihydroxy-2-(2-chlorophenyl)-8[4-(3-hydroxy-1-methyl)-piperidinyl]-4H- 1-苯并吡喃-4-酮]是一种通过IC50抑制细胞生长的黄酮类化合物 20-200 NM。最初选择它进行研究是因为它具有抗肿瘤作用。 在体内各种肺和乳腺肿瘤模型中的活性，以及作为一种 表皮生长因子受体激酶抑制剂。最近的实验表明， 药物可以使细胞停滞在G1或G2期，而G2期的发生 阻断可能与细胞内酪氨酸的磷酸化减少有关 P34cdc2激酶。进一步的实验将确定这是否是 细胞周期停滞的基础。UCN-01和UCN-02是非对映异构体， 星形孢菌素的衍生物。这些药物最初被筛选为 蛋白激酶C抑制剂，但有证据表明有抗肿瘤作用 A431鳞癌模型。最近的实验表明， UCN01和UCN02有效地抑制PKCα、β和伽马亚型， 但不是Zeta异构体。Delta型和epsilon亚型受到抑制 效力中等的。此外，该化合物的能力 抑制T细胞白血病的生长可与抑制 PKC。因此，需要考虑UCN01的额外目标。AG957 是一种具有很强抑制bcr-abl融合能力的tyrphostin 蛋白酪氨酸激酶活性在生化检测中的应用 免疫沉淀的激酶活性和活细胞中。与中国的关系 这种抑制细胞生长的活性正在研究中。

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.