PRECLINICAL AND CLINICAL PHARMACOLOGY OF PROTEIN KINASE ANTAGONISTS

开发治疗学正在开发的四种药物 计划(DTP)，NCI在本报告所述期间受到关注。 黄吡醇(Nsc-649890)，以前被定义为一种有效的直接抑制剂 细胞周期蛋白依赖性激酶(CDK)1被证明能有效抑制CDK2和CDK2 CDK4。从Hoechst印度获得的类似物将被筛选 抑制效果的选择性。UCN-01(NSC-638850)，原 作为蛋白激酶C的抑制剂提交给NCI，实际上发现了 是CDKs1和CDKs2的有效激活剂，在T淋巴母细胞中 这种激活的出现似乎与 细胞凋亡。此外，UCN-01还阻断了辐射诱导的G2 检查站，这表明它可能是同样的一个强有力的监管机构 受甲基黄嘌呤影响的检查站。因此，除了PKC之外，目标还包括 在UCN-01的行动中必须加以考虑。AG957(NSC)引线结构 用于抑制CML细胞中的BCR-ABL融合蛋白，作用于 不可逆地修饰靶向bcr-abl癌蛋白，提高 抑制机制可能涉及选择性 BCR-ABL的烷基化反应。格尔达那霉素(NSC)结合的初步证据 和氨基末端部分的格尔达那霉素可溶性衍生物(NSC) 获得了热休克蛋白HSP90。临床试验开始 持续输注(72小时)黄烷醇，前两次剂量 药物耐受性良好，达到10-50 NM的药物水平。UCN-01是 由NCI决策网络批准提交IND申请。

Four agents under development by the Developmental Therapeutics Program(DTP), NCI received attention during this report period. Flavopiridol(NSC-649890), defined previously as a potent direct inhibitor of cyclin-dependent kinase (CDK)1, was shown to inhibit potently CDK2 and CDK4. Analogs obtained from Hoechst India will be screened for selectivity of inhibitory effect. UCN-01(NSC-638850), originally presented to NCI as an inhibitor of protein kinase C, was actually found to be a potent activator of CDKs 1 and 2, and in T-lymphoblasts the appearance of this activation appeared to correlate with the onset of apoptosis. In addition, UCN-01 blocked the radiation-induced G2 checkpoint, suggesting that it may be a potent regulator of the same checkpoint affected by methylxanthines. Thus, targets in addition to PKC must be considered in the action of UCN-01. AG957(NSC) a lead structure for inhibition of the bcr-abl fusion protein in CML cells, acted to irreversibly modify the target bcr-abl oncoprotein, raising the possibility that the mechanism of inhibition may involve selective alkylation of bcr-abl. Initial evidence of binding of geldanamycin (NSC) and a geldanamycin soluble derivative (NSC) to the amino-terminal portion of the heat shock protein hsp 90 was obtained. Clinical trials commenced with continuous infusion (72hr) flavopiridol, and the first two dose levels were well tolerated with 10-50 nM drug level achieved. UCN-01 was approved by the NCI Decision Network for filing of an IND application.