STRUCTURAL STUDIES ON NATURAL PRODUCT LEADS FOR RESTORATION OF P53 FUNCTION

天然产物的结构研究有助于恢复 P53 功能

• 批准号: 6103096
• 负责人: NIKOLA PAVLETICH
• 金额: --
• 依托单位: GENZYME CORPORATION
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6103096
• 关键词: X ray crystallography; antineoplastics; biological products; chemical structure function; gene expression; gene mutation; nucleic acid structure; oncogenes; pharmacokinetics; plant extracts; structural biology; tumor suppressor genes

The goal of the NCNPDD group is to target the p53 tumor suppressor system int he screening of natural compound libraries in an attempt to identify compounds that restore the activity of p53 in tumor cells. Recent rapid advances in cancer research have identified the p53 tumor suppressor system as the body-s forefront defense against cancer. p53 is the most frequently mutated gene identified in human cancers. Mutations occur in over 50 percent of all cancer cases, and many of the remaining cases involve cellular or viral oncogenes that inactivate the p53 protein. The cellular and biochemical mechanisms mediating p53's tumor suppressing effects have recently been elucidated. At the cell biological level, p53 can induce cell cycle arrest and programmed cell death in response to DNA damage or inappropriate growth signals. At the biochemical level, p53 can bind to specific DNA sequences and activate the transcription of genes. Tumor derived p53 mutants are defective in DNA binding, and consequently they cannot induce cell cycle arrest or apoptosis. In addition to the cellular and biochemical mechanisms, the recent determination of the crystal structure of a p53-DNA complex by this laboratory has also elucidated the structural basis of p53 function. To further address issues pertaining to p53's inactivation by mutations in tumors, systematic biochemical, biophysical, and crystallographic studies of a large set of tumor derived p53 mutants will be undertaken as part of this laboratory program. The mechanism based differences between wild type and mutant p53, and in particular biochemical and structural differences, will be explored in the rational design of natural product screens in attempt to identify compounds that restore function to tumor derived p53 mutants. Lead compounds emerging from the screens will be co-crystallized in order to determine their mechanism of action, and to aid in their development into useful therapeutic agents. Structural studies will be extended to (i) the MDM2 oncogene which is p53's natural inhibitor and has been found amplified in certain tumors, and (ii) the Cip1/WAF1-cyclin-cdk complex which appears to mediate p53's growth inhibitory effects. Emphasis will be on determining their structural mechanisms of action of MDM2 and of Cip1/WAF1 to aid in the rational design of model systems to be used in the screening efforts. Lead compounds emerging from the screens will be co-crystallized in complex with their target proteins to facilitate their development into useful therapeutic agents.

NCNPDD小组的目标是针对p53肿瘤抑制系统 筛选天然化合物库以试图鉴定 恢复肿瘤细胞中 p53 活性的化合物。近期快速 癌症研究进展确定了 p53 肿瘤抑制系统 作为身体对抗癌症的最前沿防御。 p53 最常见 在人类癌症中发现了突变基因。突变发生在 50 多种 占所有癌症病例的百分比，其余许多病例涉及 使 p53 蛋白失活的细胞或病毒癌基因。蜂窝式 介导 p53 肿瘤抑制作用的生化机制 最近被阐明。在细胞生物学水平上，p53可以诱导 DNA 损伤引起的细胞周期停滞和程序性细胞死亡或 不适当的生长信号。在生化水平上，p53可以结合 特定的DNA序列并激活基因的转录。瘤 衍生的 p53 突变体在 DNA 结合方面存在缺陷，因此它们 不能诱导细胞周期停滞或凋亡。除了蜂窝 和生化机制，最近测定的晶体 该实验室对 p53-DNA 复合物的结构也阐明了 p53功能的结构基础。为进一步解决相关问题 p53因肿瘤突变而失活，系统生化， 对大量肿瘤来源的生物物理学和晶体学研究 p53 突变体将作为该实验室计划的一部分进行研究。这 野生型和突变型 p53 之间基于机制的差异，以及 特别的生化和结构差异，将在 合理设计天然产物筛选以尝试鉴定化合物 恢复肿瘤来源的 p53 突变体的功能。铅化合物 从屏幕中出现的将被共结晶以确定 它们的作用机制，并帮助它们发展成有用的 治疗剂。结构研究将扩展到 (i) MDM2 癌基因是 p53 的天然抑制剂，已被发现在 某些肿瘤，以及 (ii) Cip1/WAF1-cyclin-cdk 复合物，它似乎 介导 p53 的生长抑制作用。重点将放在确定 MDM2 和 Cip1/WAF1 的结构作用机制有助于 合理设计用于筛选工作的模型系统。 从屏幕中出现的铅化合物将以复杂的形式共结晶 与它们的目标蛋白一起促进它们发展成有用的 治疗剂。