PRECLINICAL AND CLINICAL PHARMACOLOGY OF PROTEIN KINASE ANTAGONISTS

蛋白激酶拮抗剂的临床前和临床药理学

• 批准号: 3752419
• 负责人: E SAUSVILLE
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3752419
• 关键词: Asteroidea; DNA replication; adenosine triphosphate; antineoplastics; breast neoplasms; carcinoma; cell cycle; cell growth regulation; drug screening /evaluation; enzyme inhibitors; flavones; human subject; human tissue; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; phosphorylation; protein isoforms; protein kinase; protein kinase C; protein tyrosine kinase; tissue /cell culture

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.

破坏蛋白激酶作用的试剂将是感兴趣的开发 因为蛋白激酶代表了最终的共同途径， 不同的致癌基因和生长因子。挑战在于定义 这些化合物是选择性的，但仍保持体内治疗指数。 LBC正在研究三类化合物， 用于治疗指数和潜在功效。Flavopiridol（NSC 649890; Behringwerke L 86 -8275）是一种黄酮，先前的研究表明， 各种肿瘤细胞系的生长，IC 50在20和200 nM之间， 并且可以阻断G2或G1期的细胞周期进程，以及 延缓S期进展。我们已经证明， 化合物是一种有效的p34 cdc 2激酶直接抑制剂， 乳腺癌细胞或海星星星。Ki为ATP（竞争性 抑制）为46 nM，肽底物（非竞争性）的Ki 抑制）为140 nM。此外，flavopiridol降低Thr和 p34 cdc 2的酪氨酸磷酸化。第二个正在研究的化合物是UCN- 01（NSC 638850）。这种化合物最初是作为一种选择性的 蛋白激酶C拮抗剂。我们已经证实了PKC的选择性 亚型，对PKC α、β和γ的IC 50分别为29、34和30 nM， 分别PKC δ和PKC β受影响的效力较低（ 530和590 nM），PKC zeta不受影响。的关系 细胞生长抑制与PKC抑制的关系目前正在评估中。 在评价的最后一类化合物中，我们定义了 Tyrphostin AG 957是抑制 活细胞中p210 bcr-abl酪氨酸激酶。这种效果是继 短期内通过减少DNA合成，对细胞没有立即影响 生存能力这一结果的分子基础正在研究中。